In 1988, Peligro joined the Red Hot Chili Peppers replacing drummer Jack Irons. Guitarist Hillel Slovak had recently died of a heroin overdose and was replaced by guitarist DeWayne McKnight. Peligro had been friends with the band for years and even at one point was in a joke band called Three Little Butt Hairs with singer Anthony Kiedis and bassist Flea. The McKnight and Peligro lineup didn't last long but long enough to record one track, "Blues for Meister", which appears on the Out In L.A. compilation album. McKnight was fired three shows into their tour in September 1988 and was replaced by John Frusciante, however, Peligro would last a bit longer than McKnight helping to write some songs on the band's fourth album, Mother's Milk. Peligro, who was a close friend of the band, had too many drug and alcohol issues so the band fired him in November 1988, replacing him with drummer Chad Smith who has been with the band ever since.
Peligro also played briefly with The Hellations, Jungle Studs, Nailbomb, The Feederz, Lock-Up, The Two Free Stooges and SSI. In 2001, Peligro rejoined the Dead Kennedys without former frontman and primary songwriter Jello Biafra following a civil fraud complaint against Biafra, accusing him of withholding royalties and creative privilege to license Dead Kennedys songs. In early 2008, D.H. took a hiatus from the Dead Kennedys, citing the need for time off from touring.
D.H. Peligro is the frontman for his band called Peligro (Spanish for "Danger") and has released three albums: Peligro (released in 1995 on Biafra's Alternative Tentacles record label, but deleted from the catalog in 2001), Welcome to America and Sum of Our Surroundings, which won Rock Album of the Year from the American Independent Music Awards. Peligro's sound is known to be an eclectic combination of punk, reggae, funk and heavy metal. He recently recorded a punk rock cover of Jimi Hendrix's "Purple Haze", which was nominated for a Grammy Award. D.H. Peligro has also fronted the bands Reverend Jones and the Cool Aid Choir and Al Sharpton's Hair and the Hellions. He appears as an interview subject in the 2003 documentary Afro-Punk.
Red Hot Chili Peppers were inducted into the Rock and Roll Hall of Fame on April 14, 2012. Peligro, although not inducted, was thanked by the band's longtime drummer and Peligro's replacement, Chad Smith during his speech.