The duo of Tully Blanchard and Arn Anderson made their debut late in October 1988, being under management of Bobby "The Brain" Heenan. The Brain Busters made their pay-per-view (PPV) debut at the 1988 Survivor Series in the 10 team tag match, where they eliminated the Hart Foundation, before being eliminated via double disqualification with the Rockers. This led to a match with the Rockers on WWF Superstars of Wrestling where both teams were again disqualified before the match could even get started. This kicked off a red hot series of house show matches. The teams wrestled to yet another DQ on the March 11, 1989 edition of Saturday Night's Main Event.
The Brain Busters made their first and only WrestleMania appearance at WrestleMania V against former WWF Tag Team Champions Strike Force. After an even start, the Brain Busters dominated the ex-champions as Rick Martel walked out on Tito Santana and he was brutalized and beaten after a spike piledriver and eventually pinned.
After their WrestleMania win, the Brain Busters finally got to face the WWF World Tag Team Champions Demolition and defeated them by disqualification on the May 27, 1989 edition of Saturday Night's Main Event. The Brain Busters defeated Demolition for the titles in a rematch on July 18, 1989 in a two out of three falls match. After losing the first fall, by pinfall, the Busters won the second fall, via disqualification, and won the third fall, with a distraction from Bobby Heenan and a steel chair thrown in from André the Giant, the Brain Busters ended Demolition’s record-breaking 478-day title reign. It also was the first time a title changed hands in a two-out-of-three falls match where one of the decisions ended in a disqualification. After then defeating The Hart Foundation in a non-title match at SummerSlam, they then lost the titles back to Demolition on October 2, 1989, in an equally controversial fashion as Blanchard, who was the illegal man, was pinned after receiving the Demolition Decapitation finisher. As was customary at the time, the Busters continued to defend the titles on house shows until the title change was acknowledged on television on November 4, 1989.
Their last match was a best-of-three-falls contest against The Rockers on Saturday Night's Main Event. The Brain Busters lost the first fall after not following directions from an enraged Heenan, who left the ringside area. The Brain Busters won the second fall, after which Heenan fired them during a backstage interview. The Rockers would go on to win the third and final fall of the match.
On the day of the 1989 Survivor Series, Tully Blanchard failed a drug test and the lack of a suitable replacement saw him replaced by Heenan who would wrestle for the first time since Wrestlemania V. Both Blanchard and Anderson left thereafter.