Grubbs, a former member of Squirrel Bait and Bastro, formed the band in Chicago in 1991. They released their first album, The Serpentine Similar, in 1993. This early lineup saw Grubbs joined by Bundy K. Brown and John McEntire, both members of Bastro's final incarnation, on bass guitar and drums, respectively. In 1994 Brown and McEntire left to join Tortoise and guitarist, composer and producer Jim O'Rourke joined.
At this point Gastr del Sol became mainly a collaboration between Grubbs and O'Rourke, joined by an ever-changing collection of guests. Though McEntire was no longer a full member, he continued contributing to many Gastr del Sol recordings and concerts.
Most releases by this lineup were on Chicago's Drag City Records, beginning with the acoustic guitar-based Crookt, Crackt, or Fly in 1994. "Work From Smoke", the centerpiece of this album, fused Grubbs and O'Rourke's penchant for atonal guitar interplay with bass clarinet and Grubbs's increasingly surreal lyrics.
A pair of releases followed quickly in 1995. The Mirror Repair EP added elements of electronic music. The Harp Factory on Lake Street, released on the Table of the Elements label, was their most experimental work, a piece for chamber orchestra with only occasional voice and piano from Grubbs.
1996's Upgrade & Afterlife included a would-be film score by O'Rourke, "Our Exquisite Replica of 'Eternity'", and an extended interpretation of the John Fahey piece "Dry Bones in the Valley" featuring guest Tony Conrad on violin.
With the release of Camoufleur in 1998, Gastr del Sol progressed further into the realm of conventional melodies and chamber pop, creating their most accessible and popular album. Its chord patterns, melodies, and flugelhorn and string-heavy arrangements prefigure O'Rourke's future pop releases. The album was co-written with Markus Popp, of the pioneering German glitch group Oval, who contributed to the electronic aspects of the album.
After Camoufleur the band split up. Grubbs and O'Rourke have both continued to release albums under their own names in the fields of rock, pop, and experimental music.