In 2006, approximately seven or eight months after Eddie's death, Vickie started appearing more prominently in more controversial storylines. She first asserted herself during a feud between Mysterio and Chavo Guerrero when Chavo accused Mysterio of being "nothing but a leech living off the blood of the Guerrero name" on the August 4 episode of SmackDown!. Subsequently, she acted as peacemaker between the two former friends until she seemingly inadvertently interfered in their match at SummerSlam in 2006, costing Mysterio the match. She then officially betrayed him by siding with Chavo and hitting Mysterio in the back with a steel chair on the following episode of SmackDown!, becoming a heel in the process. On the September 1 episode of SmackDown!, she declared herself Chavo's business manager and Mysterio an "insignificant chapter" in her past. At No Mercy, Chavo lost to Mysterio in a Falls Count Anywhere match. On October 20, Rey Mysterio lost an "I Quit" match against Chavo after interference from Vickie.
On October 27, 2006, Chris Benoit became involved in the storyline. He tried to figure out what Vickie was doing with Eddie's estate while also defending the WWE United States Championship in a rivalry with Chavo. At Survivor Series, Chavo kicked out of an attempted sharpshooter, causing Benoit to knock Vickie off the ring apron and on her head, causing her to begin to wear a neck brace and blame Benoit for "intentionally" hitting her. At the end of December, she interfered in a United States Championship match between Chavo and Benoit, which caused Chavo to lose and Benoit to retain the title. As a result, Chavo shouted "If you wanted me to win the title, then stop getting me disqualified," before pushing Vickie over.
In May 2007, Kristal, the on-screen girlfriend of General Manager Theodore Long, convinced him to give Guerrero an interview for the position as his assistant. A week after the interview, Vickie was given the job. On the June 29 episode of SmackDown!, Vickie acted as interim general manager of SmackDown! while Long was planning his wedding with Kristal. She was soon named the maid of honor at Long and Kristal's "wedding". On the September 21 episode of SmackDown!, Long suffered a kayfabe heart attack during his wedding to Kristal before they had legally wed. The following week, Vince McMahon named Vickie the new General Manager. On the November 23 episode of SmackDown!, she "punished" Edge for his interference in the championship match at the Survivor Series by making him the number one contender for the World Heavyweight Championship, before revealing that she had begun a romantic relationship with him and had facilitated his "plan" to regain the belt. Later in the night, as she stood alone in the ring, after watching Chavo be attacked by the Undertaker. He performed a Tombstone Piledriver on Vickie. After being off-air for several weeks, she returned on December 14 as a villain and in a wheelchair, making biased matches in favor of Edge which led to him winning the World Heavyweight Championship at Armageddon.
In early 2008, she formed La Familia with her nephew Chavo, Edge, the team of Curt Hawkins and Zack Ryder, and later, Bam Neely. One of her first acts as part of the new group was to help Chavo win the ECW Championship from CM Punk. At the Royal Rumble, Vickie interfered in the World Heavyweight Championship match between Edge and Rey Mysterio, allowing Edge to retain his title. On the subsequent airing of SmackDown, Edge proposed to Vickie, who accepted, but the event was interrupted by Mysterio. After Vickie had helped Edge to retain his championship for almost 4 months, he eventually dropped the title to The Undertaker. This started a feud between Edge and the Undertaker, with Vickie giving Edge numerous title opportunities and placing The Undertaker in difficult matches. On the May 2 episode of SmackDown, she stripped The Undertaker of his championship after deciding that his new gogoplata (dubbed Hell's Gate) submission hold was too dangerous and made a match between The Undertaker and Edge for the vacant title with the stipulation that Undertaker would be banished from WWE if he lost. Following interference, Edge won the match and Vickie 'banished' Undertaker. However, Edge lost his title shortly afterwards to CM Punk. On the July 4 episode of SmackDown, Edge took his frustrations for losing the World Heavyweight Championship out on Vickie by telling her the wedding was off. The next week, however, Edge re-proposed to Vickie after SmackDown! had gone off the air.
On July 18, at the wedding reception (the wedding had occurred off-screen before the show) Triple H came out and showed a video of Edge cheating on Vickie the day before with Alicia Fox, the wedding planner. The storyline continued at The Great American Bash when Fox attempted to hand Edge the WWE Championship belt to use as weapon, but was stopped with a clothesline by Vickie. Edge attempted to spear the referee to delay the match, but hit Vickie instead. Triple H used this distraction to recover and hit a Pedigree to retain his title. On the July 25 episode of SmackDown, Edge attempted to get Vickie to forgive him, but instead she announced the reinstatement of his former enemy The Undertaker, whom Edge would face at SummerSlam in a Hell in a Cell match, turning her face for the first time since 2006. A few weeks later, as revenge, Edge attacked the members of La Familia and tipped Vickie from her wheelchair. The Undertaker refused to accept her apology for his banishment, but Vickie stated that she was not afraid of him. She also stated that at Unforgiven, she would force him to apologize to her, but at Unforgiven when The Undertaker did not comply, the Big Show knocked him out and Vickie spat in his face. Big Show then aligned himself with Vickie, and for the next two weeks they continued to gloat at how they beat The Undertaker. After Undertaker attacked Chavo, Vickie pleaded with Undertaker for forgiveness for her actions. Undertaker, however, once again hit her with a Tombstone Piledriver, forcing Vickie to rely on both a neckbrace and a wheelchair again. Over the following weeks, Vickie put the Undertaker in matches against the Big Show that seemed impossible for him to win. The feud ended after Big Show lost to Undertaker in a casket match.
At Survivor Series, during a match for the WWE Championship between the champion Triple H and Vladimir Kozlov, Vickie came out to the arena making the announcement that "he's here". Edge's music was played and he came out to compete, making it a triple threat match. At the end, he won the championship, and as he went to the back, he greeted Vickie with a hug. On the December 5 episode of SmackDown they shared a kiss, thus reinstating their on-screen relationship. On the special December 8 episode of Raw, Vickie and Edge won a Slammy Award for the Couple of the Year.
On February 23, 2009, she was appointed the interim General Manager of Raw during Stephanie McMahon's absence. On the following episode of Raw, Guerrero announced that Edge would be facing The Big Show for his World Heavyweight Championship at WrestleMania XXV. On the March 9 episode of Raw, John Cena showed footage of Vickie cheating on Edge with Big Show after Guerrero had added Cena to the World Heavyweight Title match through blackmail of revealing the secret affair, making it a triple threat in the process. At WrestleMania XXV, Edge lost the World Heavyweight title to Cena after Cena pinned Show after Cena delivered the Attitude Adjustment to Edge onto the Big Show. On the April 6 episode of Raw, Guerrero was given the choice of either being General Manager of Raw or SmackDown. She then announced that she would move to Raw in order to become its new General Manager, subsequently resulting in her being separated from Edge. However, The Big Show and her nephew Chavo were also moved to Raw during the 2009 WWE Draft and Supplemental Draft, respectively.
After being insulted for a few weeks by being made fun out of her weight by Santino Marella, Vickie, with help from William Regal, won the "Miss WrestleMania" crown from Santina Marella, Santino's "twin sister", in a no disqualification match sanctioned by Chavo on the May 18 episode of Raw. On June 7 at the Extreme Rules pay-per-view, Vickie lost her "Miss WrestleMania" title to Santina in a hogpen match with Chavo Guerrero by her side. The following night on Raw, Vickie announced her resignation as Raw's General Manager. After her announcement, Edge came out and told Vickie that he was sorry for saying disrespectful things about her, only to reveal that he only married her so she could help him in World Championship matches, and now that she quit, she was useless to him in his endeavors to become the champion again. He then told Vickie that he wanted a divorce, leading to her suffering from a nervous breakdown. In reality, Vickie had requested to leave WWE so that she could spend more time with her family.
Guerrero returned to WWE on the SmackDown 10th Anniversary special episode on October 2, where she introduced her storyline boyfriend, then-heel, Eric Escobar, who she would be managing on the SmackDown brand. On the November 20 episode of SmackDown, Guerrero was named as a SmackDown consultant by WWE Chairman Vince McMahon. The following week after Escobar failed to capture the Intercontinental title from John Morrison, Vickie ended their relationship. Escobar claimed that he could not take it any longer, saying he only went out with her for power, mirroring what Edge admitted as to why he had married Vickie on the June 8 episode of Raw. Guerrero then put him in a handicap match with The Hart Dynasty the following week and the week after put him in another handicap match against Chris Jericho and Big Show. The storyline was soon dropped when Escobar was released by WWE.
Guerrero began involving herself in the already heated rivalry between WWE Women's Champion Mickie James and Michelle McCool and Layla, taking the sides of Team Lay-Cool after Mickie accidentally doused her with cottage cheese. On the February 26 episode of SmackDown, Guerrero acted as Special Guest Referee for a title match between James and McCool, ultimately costing James the title after slapping her. Two weeks later she got involved in a match between WWE Women's Champion Michelle McCool and Tiffany causing Tiffany to win the match by DQ. After the match, Michelle McCool and Layla began to beat down Tiffany until Beth Phoenix made the save, in the process delivering a clothesline to Vickie Guerrero. Two weeks later Guerrerro appeared in a 5-on-1 handicap match with Alicia Fox, Maryse and Team LayCool against Beth Phoenix. Guerrero mainly hid behind Alicia Fox, Maryse, and Team LayCool, letting her partners do the dirty work until Phoenix was weakened and Guerrero made the pin, winning the match. It was announced after that she would compete in a ten diva tag team match at WrestleMania. At the WrestleMania XXVI 10-Diva Tag Match, Guerrero's team was victorious when Guererro herself climbed the turnbuckle and gesturing to the sky connected a "frog splash" in an apparent tribute to her late husband Eddie. On the May 10 episode of Raw, Guerrero was named the permanent general manager of the Raw brand for the second time, but then resigned on the same night after being intimidated by Randy Orton. Although not the general manager, she returned to SmackDown as the Consultant on the May 14 episode and forced Phoenix to face Team Lay-Cool in a handicap match, which Layla won to achieve her first WWE Women's Championship.
In June she began a romance storyline with Dolph Ziggler and began accompanying him to the ring. On the August 31 episode of WWE NXT, it was announced that Vickie Guerrero would be the pro originally for the rookie Aloisia in the Season 3 Diva's edition of NXT, but due to certain circumstances, Aloisia was sent to FCW, and was later released. Vickie was assigned a new NXT rookie, Kaitlyn which she begin a feud with. On October 5, she was defeated by Kaitlyn in a rookie versus pro match. Kaitlyn was caught backstage kissing Vickie's boyfriend Dolph, which added more fuel to the fire. Kaitlyn went on to win NXT and later joined SmackDown.
In January, she became the acting General Manager of SmackDown after Theodore Long was found unconscious backstage. At the Royal Rumble pay-per-view, Kelly Kelly attacked Guerrero during the Edge vs. Dolph Ziggler match. On the February 4 episode of SmackDown, Ziggler and Lay-Cool lost to Edge and Kelly in a two-on-three handicapped mix tag match for the World Heavyweight Championship. At the end of the match, Guerrero fired Kelly, and announced a championship match between Edge and Ziggler, and that Guerrero will be the special guest referee of the match. The following week, while officiating the world championship match, she attempted to use the spear but failed to use it to Edge and kay-fabe injuring her ankle. While Vickie was down, Clay Matthews of the Green Bay Packers replaced Vickie as referee. While she was down, Edge speared Ziggler even though the spear was still banned but it should not have been banned. Edge won the match but a laid down Vickie insisted that Edge did not retain the title. On Smackdown's 600th episode the following week, she stripped Edge for the title and fired him. Later that night, there was a coronation for Dolph Ziggler as World Heavyweight Champion. However, the returning Theodore Long revealed that he was once again in charge and that Vickie and Dolph were the culprits behind his assault, thus making an impromptu match between Dolph and a reinstated Edge for the World Heavyweight Championship, in which Edge won. After the match, Long fired Dolph (kayfabe) from the WWE. As a result of Dolph being fired, his spot in the World Heavyweight Championship Elimination Chamber match at the upcoming Elimination Chamber event was vacated. At the event, Big Show was revealed as his replacement. On the February 25, 2011 episode of SmackDown, Theodore Long announced that a match would take place with Edge and Kelly Kelly facing Vickie and Drew McIntyre. Vickie lost the match, and was then fired (kayfabe) from her role as official consultant by Teddy Long.
On the March 7, 2011 episode of Raw, Guerrero and Ziggler made their return to the brand, with Vickie managing him in a singles match defeating John Morrison. After the match, the anonymous Raw General Manager informed Vickie that Dolph Ziggler had indeed been hired, but they did not hire her yet. The general manager then continued by issuing a match between her and Trish Stratus for the following week, with the stipulation being if Vickie wins, she would be hired. The following week, Vickie defeated Trish in a No Disqualification match with the help of team Lay-Cool.
Right after defeating Stratus in the No Disqualification match, Guerrero challenged Stratus, John Morrison, and that week's Raw guest star Snooki, who had slapped Guerrero earlier in the night, to a six person mixed tag team match against Lay-Cool and Ziggler at WrestleMania XXVII in which the trio accepted. On the March 21, 2011 episode of Raw, Guerrero, LayCool, and Ziggler lost to Stratus and Morrison in a 4-on-2 handicap match. At WrestleMania XXVII, Vickie Guerrero's team of Lay-Cool and Ziggler were defeated by Snooki, Stratus, and Morrison.
While still being the manager and kayfabe "girlfriend" of Dolph Ziggler since the loss at WrestleMania XXVII, Vickie appeared as Tyson Kidd's manager for the June 9, 2011 episode of Superstars, only for Kidd to be defeated by Yoshi Tatsu. During this time period, Kidd had been looking for a manager to lead him to success, giving chances to several past and present WWE talents. This was the only time Guerrero had managed Kidd, and went on to continue her storyline involvement with Ziggler.
At the Capitol Punishment PPV, Dolph Ziggler won the United States Championship from Kofi Kingston, with the help of Guerrero. On the next nights episode of Raw, Ziggler retained the championship from Kingston by disqualification. On the same night, Vickie would then go on to lose the dance contest to Michael Cole, despite Cole receiving the most boos. Even after kissing Matt Striker while dancing, Cole would go on to win via impersonation. On the September 19 episode of Raw after weeks of pursuing for Vickie's services, Jack Swagger finally convinced Vickie to sign a managerial contract. At Tables, Ladders & Chairs, Ziggler lost the United States Championship to Zack Ryder, who would lose the title to Swagger on the January 16, 2012, edition of Raw. On the March 5 episode of Raw, Swagger lost the United States Championship to Santino Marella. On the June 18 episode of Raw, Vickie Guerrero ended her clientele service with Jack Swagger and renewed her romantic relationship with Ziggler. After showing "evidence" to the WWE Board of Directors of AJ Lee "fraternizing" with a WWE Superstar - which was later stated as John Cena - Lee was asked to resign, making Guerrero Managing Supervisor on October 29.
On December 17, Guerrero teamed up with John Cena on the annual Slammy Awards episode of Raw to face AJ Lee & Dolph Ziggler, in retaliation for Ziggler ending their business relationship. On the February 18th episode of WWE Raw, Guerrero named Brad Maddox as her assistant. She announced that Dolph Ziggler, former protégé, will defend the World Heavyweight Championship In a triple threat match at Extreme Rules against Alberto Del Rio, the man that lost his world title to Dolph, and Vickie's other protégé, Jack Swagger in a ladder match for the World Heavyweight Championship. Guerrero would start this angle where Vince, Stephanie, and Triple H would all pressure Vickie to increase the level of her authority. On the July 1st episode of Raw, Stephanie McMahon announced that Vickie would have a job evaluation the next week on Raw. On the July 8th episode of Raw, the fans voted Vickie Guerrero as failing therefore resulting in getting fired by Stephanie. Vince tried his best to console her and appointed Brad Maddox as the new General Manager in order to "kill the show" because of what the people had done to Vickie.
On the July 19, 2013 SmackDown Vince McMahon hired Guerrero as the new General Manager of SmackDown. Vickie tells the fans she hated each and every one of them, blaming them for her getting fired as managing supervisor of Raw. In addition to this, when Brad Maddox congratulated her, Vickie slapped him, and in revenge for having security escort her out by Teddy Long's orders the week before, Vickie had Long escorted out by security. On the October 7th edition of Raw, Vickie distracted Alberto Del Rio in his match with Ricardo Rodriguez allowing Ricardo to pick up the win, after announcing that Alberto Del Rio will defend the World Heavyweight Championship against John Cena at Hell in a Cell. Vickie implied a face turn on the October 12th edition of SmackDown after ridiculing Del Rio, who tried to find a way out of his championship match against Cena. On the November 18th edition of Raw, Vickie was forced to compete in a match against the Divas Champion AJ Lee. In attempt to get out of this, she unsuccessfully faked an injury and was forced to compete by Stephanie McMahon. Additionally, Vickie faked a fainting spell which did not work either and tried to escape by running away but AJ dragged her back to the ring and put her in the Black Widow and Vickie immediately submitted. On the March 24th edition of Raw, after hearing insulting comments from AJ about her, Vickie announced that AJ would defend her Divas Championship in a "14 Diva Vickie Guerrero Invitational" at WrestleMania XXX.
On the June 16 episode of Raw, Roman Reigns tried to convince Vickie to put him into the battle royal for a WWE World Heavyweight Championship opportunity at Money in the Bank pay-per-view, Vickie however refused, because The Authority didn't allow him in it. Reigns then spiked the coffee she gave to Stephanie McMahon, causing Stephanie to throw up on Vickie and leave with Triple H to the hospital. Vickie later gave Reigns a chance in the battle royal, which he would win. On June 23 episode of Raw, Vickie lost in a pudding match against Stephanie McMahon with her job on the line, after interference by Alicia Fox, Layla and Rosa Mendes. Vickie ultimately lost the match and was fired, however she got her retribution over McMahon by throwing her into the mud pool and mouthed, "this was for you"; a tribute to her late husband, Eddie Guerrero, also taunting like Eddie while leaving the ring, turning Vickie face for the first time in almost seven years, as well as being cheered. This was done to write her off television having requested her release a few months before.