The bandmembers were having problems with their singer at the time, Chuck Mosley, and gave a careful listen to a Mr. Bungle demo that Patton gave the group. They were blown away. When Mosley finally got the boot a short time later, the band set out to find a replacement. Since Patton was quite content with being a college student and playing with Mr. Bungle, he didn't exactly jump at the invitation (interestingly, the band also asked Chris Cornell of Soundgarden). Eventually he did change his mind, but made it clear that he would be a member of Faith No More and Mr. Bungle.

Patton proved to be an important addition to FNM, as they gained worldwide recognition with releases like The Real Thing, Angel Dust, and Album of the Year. Mr. Bungle signed to Warner Bros., due in part to Patton's newfound fame, and released their self-titled debut in 1991 (produced by experimentalist John Zorn) and the critically acclaimed Disco Volante in 1995. Although they didn't acquired massive FNM-like success, they obtained a loyal and constantly growing fan base. Patton continued to work with John Zorn, releasing a pair of solo albums for Zorn's Tzadik label, in addition to guesting on tracks by Sepultura, the Kronos Quartet, and the Boo-Yaa T.R.I.B.E., among others.

A year after Faith No More called it a day in mid-1998, Patton launched his own record label, Ipecac. The label's first release was the self-titled debut by the Patton-led, all-star experimental outfit Fantômas, who also included former Slayer drummer Dave Lombardo, Melvins guitarist Buzz Osbourne, and Mr. Bungle bassist Trevor Dunn. Patton then returned to Mr. Bungle, contributing to one of their finest albums, the Beach Boys-tinged California. He subsequently joined ex-Jesus Lizard guitarist Duane Denison's Tomahawk (featuring ex-Helmet drummer John Stanier and Melvins bassist Kevin Rutmanis) and formed the R&B/pop/electronic experiment Lovage (a collaboration with hip-hop producer the Automator). He also contributed tracks to Tzadik Records' tributes to Burt Bacharach, Serge Gainsbourg, and Marc Bolan.

A number of recordings featuring Patton saw release in 2001, including Fantômas' sophomore effort, The Director's Cut; the debut recording of Tomahawk; and a collaboration with Dan the Automator on the Lovage album. Lovage were met with great enthusiasm by new audiences, inspiring Dan the Automator and Patton to collaborate on more songs throughout 2002 for a Peeping Tom album. And when old friends Dillinger Escape Plan found themselves without a singer that spring, Patton stepped up and helped them put together a new EP, even continuing as a temporary singer after they had filled the position. After six years of perfecting Patton's warped take on a pop album, Peeping Tom was finally released in May of 2006.

Patton also tried his hand at acting in such motion picture projects as Firecracker and Amnesia, and continued to develop his interests outside the music studio, providing voices for the video games The Darkness, The Portal, Left 4 Dead, and Bionic Commando, and using his guttural vocal roars to provide vocals for the creatures in I Am Legend. In 2008, he composed a soundtrack for the Derrick Scocchera independent film A Perfect Place, released on Ipecac. A long-planned album of big-band ‘50s and ‘60s Italian crooner covers followed in 2010, titled Mondo Cane.