Holton's most famous role may be that of Francis Buxton, Pee-Wee Herman's nemesis, in the 1985 blockbuster Pee-wee's Big Adventure. He also played Chubby in the werewolf comedies Teen Wolf and Teen Wolf Too. The 1990s found another main role awarded to Holton, as Ozzie in the first Leprechaun horror film. In 2003, Holton performed in first starring role: that of real-life serial killer John Wayne Gacy in Gacy.
He performed as the adult version of the bratty Stillwell in the closing scenes of 1992's A League of Their Own. Other feature films in which he had minor roles include The Naked Gun: From the Files of Police Squad! (in which he utters the memorable line, "Hey, it's Enrico Palazzo!"), My Life, Little Giants (his next Sports movie after A League of Their Own, as Zolteck's dad), and the 2000 live-action/animated film adaptation of The Adventures of Rocky and Bullwinkle.
