Sisto continued his stint at The Goodman, starring opposite Brian Dennehy in Bertolt Brecht’s "Galileo.” He soon made his feature film debut, playing the son of Kevin Kline and Mary McDonnell in Lawrence Kasdan's ensemble drama "Grand Canyon" (1991). After a supporting role in "Desperate Choices: To Save My Child" (NBC, 1992), Sisto relocated to Los Angeles once he graduated high school and shortly thereafter tackled the challenging of playing an epileptic and mentally-challenged teenager in a stage production of "The Care and Custody of Barbara Moon," a choice made out of initially being unable to find onscreen work. He stayed patient, however, studying his craft with Howard Fine and finally breaking through with parts in the remake of "The Shaggy Dog" (1994), the low-budget thriller "The Crew" (1994) and the dismal serial killer suspensor "Hideaway" (1995).

Both thrillers mined the dark side of Sisto's persona. "The Crew" cast him as a sexually confused young man who holds six people at gun point on an isolated boat, while "Hideaway,” adapted from Dean Koontz's best-seller, saw him portray a satanic serial killer who is psychically connected to an antiques dealer (Jeff Goldblum). On a lighter note, he reunited with “Hideaway” star Alicia Silverstone to enjoy his first hit with Amy Heckerling's teen comedy "Clueless" (1995), playing Elton, a spoiled brat who is set up with the misfit pal of a popular rich kid (Silverstone). Sisto next appeared as Gwyneth Paltrow's love interest in the female-driven "Moonlight and Valentino" (1995) before delivering another edgy performance as an angry, insecure teen coping with his overbearing father in Ridley Scott's sea-going actioner "White Squall" (1996). Similarly, he appeared in the smart, black comedy-thriller "Suicide Kings" (1997) as a morphine-addicted medical student who helps kidnap a local kingpin (Christopher Walken) and practices his surgical technique by removing one of the mobster's fingers.

In preparation for his role as distance runner Frank Shorter in "Without Limits" (1998), Sisto trained several weeks before production with an Olympic coach. That year also offered him in a comic turn as the pot-smoking gay lover of Andy Dick in the festival-screened "Bongwater.” He gave a soulful performance in "This Space Between Us" (1999), playing a Hollywood screenwriter who returns to his quirky Northern California home town following the untimely death of his wife. In NBC’s two-part miniseries "The '60s" (1999), Sisto landed the role of Kenny Klein, an intense student activist whose zeal leads him to a tragic end. He had perhaps his highest profile role yet, however, in the title role of the CBS miniseries "Jesus" (2000). Despite having little time to prepare—he was on a plane the day after being cast—Sisto pulled off a performance that has proven difficult for other actors, one that was even blessed by the late Pope John Paul II.

Sisto continued to work regularly in supporting roles, appearing in films such as "Angel Eyes" (2001), before he made a major mark with a recurring stint on writer Alan Ball's dark, seriocomic HBO series "Six Feet Under" (2001-2005), playing the mentally unstable Billy Chenowith, the troubled brother of Brenda (Rachel Griffiths) who harbors an unhealthy obsession with his sister. Further appearances in unremarkable films were followed by a prominent role in the flawed historical miniseries "Caesar" (TNT, 2002), playing the titular Roman dictator. His next major turn was in the harrowing teen angst film "Thirteen" (2003), playing Holly Hunter's uninvolved beau. Sisto followed with several low-budget films that were hardly released—“Manifest” (2003), “In Enemy Hands” (2004) and “Dead and Breakfast” (2004) to name a few—before he returned to commercial fare with a supporting role in the Ashton Kutcher-Amanda Peet romantic comedy, “A Lot Like Love” (2005).

Following another trip to low-budget indie territory with a supporting role as the Handcuffed Man in the gripping thriller, “Unknown” (2006), Sisto returned to regular television work with a leading role in the short-lived, “Kidnapped” (NBC, 2006-2007), a serial drama that followed a private investigator (Sisto) trying to find the abducted teenaged son (Will Denton) of a wealthy couple. The series was canceled after airing only five episodes. Meanwhile, Sisto gave a fine performance in the late Adrienne Shelly’s hopeful dark comedy, “Waitress” (2007), playing the loutish husband of a pregnant pie maker (Keri Russell) using her special talents to find the right recipe for love. “Waitress” premiered at the 2007 Sundance Film Festival amidst praise and tears—director Shelly was murdered in her New York City apartment in November 2006 never having known her film made it into the festival, let alone being picked up for distribution.