The Pixies were active from 1986 to 1992. They found modest success (primarily on college radio) in America and became very popular in Britain and throughout Europe. They have retained a following, and have since been seen as one of the best and most influential rock groups of their era.

After the band split (due primarily to internal tensions between Thompson and bassist/singer Kim Deal), he went on to record solo material with Eric Drew Feldman, a member of alt rock pioneers Pere Ubu who also appeared on Captain Beefheart's Doc at the Radar Station and Ice Cream for Crow albums. After adopting the stage name "Frank Black" (a reversal of his "Black Francis" persona), his first solo release was the self-titled Frank Black (1993), which included the song "Los Angeles" (about different places named Los Angeles - "not the one in south California / they got one in south Patagonia"), and this was followed in the next year by Teenager of the Year, which included the song "Headache." These two albums were critically well-received and remain fan favorites, although they enjoyed little commercial success.

1996 saw the release of The Cult of Ray, which featured Lyle Workman on lead guitar. A point of interest here is that Workman's guitar was fed solely through the left speaker, with Thompson's rhythm coming from the right. Despite the likeness between Workman and Santiago's berserk styles, the album did not gain the same critical or fan acclaim as his previous solo efforts. Recently, Workman has continued his career by touring with Beck. Following this album, Thompson formed a new band, Frank Black and the Catholics, featuring Rich Gilbert (guitar, pedal guitar and keyboards) and Cult of Ray musicians David McCaffrey (bass) and Scott Boutier (drums). The band's eponymous first album Frank Black and the Catholics was released in 1998. This was the first Frank Black album recorded entirely to two-track live in the studio, which would become a signature of future albums released by the band. This was the first album ever posted on eMusic and, according to the website, is arguably the first album ever made legally available for commercial download.

The new band also released Pistolero in 1999 and then Dog in the Sand, which is often considered a high-point of Thompson's career, in 2000. This album added Athens, Georgia musician Dave Philips on pedal steel guitar and lead guitar, and also saw the return of Joey Santiago on three tracks. Two separate albums, Black Letter Days (the title refers to the opposite of "Red Letter Days" which are holidays - a "black letter day" being an ordinary day ) and Devil's Workshop, were released simultaneously in 2002; this was considered to be a somewhat unusual, although musically successful, move. A sixth album with the Catholics, Show Me Your Tears, was released in 2003. "Show Me Your Tears's" title and many of the songs in it were inspired by Thompson's recent divorce.

In late 2003, following long-standing rumours, an official announcement was made that the Pixies were practicing for a reunion tour. They played publicly for the first time in 12 years in April 2004, and went on to tour extensively in the U.S, Canada and Europe in the same year. The Pixies also recorded a new composition "Bam Thwok", sung and co-written by Kim Deal, which was released on the iTunes Music Store.

As far as recording was concerned, 2004 saw Thompson step way from his regular backing band The Catholics to collaborate with other musicians in Nashville. Thompson teamed up with legendary session men Steve Cropper, Spooner Oldham, Reggie Young, and Anton Fig, as well as producer Jon Tiven, to record Honeycomb, his first solo album since 1996's Cult of Ray. Honeycomb was released in July 2005 to very favorable reviews.

Thompson continued to tour with the Pixies through 2005 and 2006, but also recorded more solo sessions which are to be joined with unreleased tracks from the Honeycomb tapes for a new double album called Fastman Raiderman (due for release in June 2006). In addition, two separate albums of Frank Black and the Catholics b-sides and rarities, Snake Oil and One More Road for the Hit, were released on iTunes in March 2006 (with an eye towards a future CD release). On top of this, Thomson was also working on more new solo material with Eric Drew Feldman in the first part of 2006, some of which has already been performed live with Feldman at small concert halls.

He is currently married to his second wife Violet Clark, with whom he has two children, Jack and Lucy.