PRIMUS is the band that composed and performed the South Park Theme, and the frontman of the group, Les Claypool sings the song. Les Claypool is somewhat a South Park character as well, with a few appearances on the show. He appears in the opening, singing the theme song in most of the episodes of the show from seasons 1-4 ("Cartman Gets an Anal Probe" to "Do The Handicapped Go To Hell?") He also appears on the intro when the show airs in syndication.
PRIMUS performed "South Park Theme" and "Mephisto and Kevin" on Chef Aid: The South Park Album.
PRIMUS' song "John the Fisherman" was played in the episode, "Guitar Queer-o". While studying the nature of existence, Kyle has a psychedelic experience while the song "Welcome To This World" is played in Tooth Fairy Tats 2000.