Sisto played a killer in "Hideaway," a rich brat in "Clueless" and "White Squall," Jesus in the eponymous mini-series, a patient diagnosed with multiple personality disorder in the short film "Inside," a former drug addict in "Thirteen," and an abusive husband in "Waitress." Sisto also played the character "Billy" in the HBO series "Six Feet Under." He also appeared in the 2003 of the WB's "Dawson's Creek."

Besides acting, Sisto has worked behind the scenes. In 1998, he produced the unreleased movie "Taken," together with his friend Ethan Embry. He also produced the films "Three Women of Pain" and "Paranoia 1.0." In April 2003, he started his own production company, Dima Entertainment. In 2006, he appeared on Broadway in Festen. In the same year, he starred in the short-lived NBC drama series Kidnapped.

In 2008, Sisto joined the cast of the crime drama "Law & Order" as Detective Cyrus Lupo, replacing the outgoing Milena Govich. He had previously appeared on the show as a lawyer in the previous season's finale.

Sisto is currently starring in the American television comedy series "Suburgatory" which premiered on ABC in the fall of 2011.