Setzer was born in Massapequa, New York. Beginning in January 1979, he has fronted the popular rockabilly band, the Stray Cats.

After performing locally from New York to Philadelphia under various band names with no real success, singer and lead guitarist Setzer, drummer Slim Jim Phantom (born James McDonnell) and bassist Lee Rocker (born Leon Drucker) decided in June 1980 to go to London, England where they believed people would better appreciate their sound and style.

To get the money for their plane tickets, Brian, Lee and Jim went to Sam Ash Music on 48th Street to sell their instruments and gear to the store, and rather than negotiating simply sold all of their equipment for just enough money for three one-way plane tickets. Upon their arrival, they decided to call themselves the "Stray Cats", a name suggested by Rocker because of their status as 'strays'. After performing for only a few months they drew the attention of British producer Dave Edmunds and released a series of successful singles in the UK, which countered the already-entrenched punk scene in London with the more simple stripped down rockabilly sound, which immediately caught on with the youth.

After releasing several singles and two albums in England, the Stray Cats finally caught America's attention with the 1982 album Built for Speed, which included the two Top Ten hits, "Rock This Town" (#9) and "Stray Cat Strut" (#3). This album was basically a re-release of many of the songs from the two previous albums: the self-titled "Stray Cats" and "Gonna Ball" (they have never been released in America). Their follow-up 1983 album Rant 'N Rave with the Stray Cats included the two successful singles: "(She's) Sexy + 17" (#5), and "I Won't Stand In Your Way" (#35).

After only four years, the Stray Cats separated in 1984, but reunited briefly to record albums and mount tours several times all the way through the early 1990s. From 1985 to early 1986, Setzer was the lead guitarist for the touring version of Robert Plant's ensemble band, The Honeydrippers.

In the summer of 1986, Setzer released his first solo album, The Knife Feels Like Justice, which marked a huge move away from his trademark sound and towards a more mainstream 'rock-roots' sound, which was popularized at the time by such other artists such as John Cougar Mellencamp and Bruce Springsteen. The album was given very little promotion by his label and as a result it only found minor success, peaking at only number 45 on the Billboard US album charts. The album has become a cult favorite among those who understood the message Setzer was trying to attempt, such as the world's nuclear proliferation, the immigration issue, the understanding of religion and the 'working man's blues', such as unemployment, loneliness, etc.

In 1987, Setzer played the part of Eddie Cochran in the biographical film on the life of Ritchie Valens, La Bamba.

In the mid-1990s Setzer once again resurrected an older form of youth-oriented music, swing and jump blues music, when he formed The Brian Setzer Orchestra, an ambitious 17-piece ensemble project, which released four studio albums, a Christmas disc and several live releases between 1994 and 2002. His group's biggest success (and Setzer's outside the Stray Cats) came in 1998 with the release of the album The Dirty Boogie which cracked the top ten on the US album charts and featured a hit single, a cover of Louis Prima's "Jump, Jive and Wail".
 
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