Stamatopoulos had written a spec script for a Simpsons episode out of love for the show, and Andy Dick convinced him to submit it to The Ben Stiller Show, which got him hired. He met and worked with Bob Odenkirk. After Stiller's show was canceled, he moved to New York City, where he wrote during the 1990s for The Dana Carvey Show, Late Night with Conan O'Brien (also with Odenkirk), Late Show with David Letterman, Mr. Show with Bob and David.
In 2000 Stamatopoulos and Robert Smigel pitched Comedy Central a spin-off of Smigel's TV Funhouse cartoons (which were appearing singly as animated shorts on Saturday Night Live episodes) as a half-hour Sketch comedy show. The standalone TV Funhouse show premiered in 2000 but was canceled after one season. He later joined the writing staff on Mad TV.
Stamatopoulos worked as a creative consultant and contributing Writer on the first season of Tom Goes to the Mayor, with Tim & Eric and Bob Odenkirk. He also provided the voice of Drinky Crow on The Drinky Crow Show, which aired for one season on Adult Swim. His stop motion animated series Moral Orel premiered on Adult Swim on Christmas 2005 and aired for three seasons, airing its final episode in December 2008; a follow-up special aired in 2012. Following Moral Orel, Stamatopoulos created Mary Shelley's Frankenhole, a stop motion series, for Adult Swim. It ran for two seasons from 2010 to 2012.
A long-time fan of radio personality Steve Dahl, Stamatopoulos hosted a podcast, Sorry About Everything, from May 2012 until June 2013 on Dahl's Steve Dahl Network.
Stamatopoulos and friend Andy Dick host a weekly podcast, Dino and Andy's Skull Juice, premiering in late 2016 and is produced by Feral Audio.