Willis also regularly does studio voice work and writes compositions for films. He also creates solo music and leads The Ike Willis Band. He has released two solo studio albums under his own name and is working on another album.
Willis met Zappa during a 1977 concert at his school, Washington University, in St. Louis, his hometown. "Black Napkins," a track from the 1976 album Zoot Allures, was one of the first Zappa songs that made a deep impression on the singer.
The triple album Joe's Garage featured lead singer Ike Willis as the voice of the character "Joe" in a rock opera about the danger of political systems, and the suppression of freedom of speech and music - inspired in part by the Iranian Revolution that had made music illegal within its jurisdiction at the time - and about the "strange relationship Americans have with sex and sexual frankness". The album contains rock songs like "Catholic Girls" (a riposte to the controversies of "Jewish Princess"), "Lucille Has Messed My Mind Up", and the title track, as well as extended live-recorded guitar improvisations combined with a studio backup band dominated by drummer Vinnie Colaiuta (with whom Zappa had a particularly good musical rapport). On some of the tracks Zappa superimposes material recorded in different time signatures, a process he termed xenochrony. The album contains one of Zappa's signature guitar pieces, "Watermelon in Easter Hay".

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