Nominated six times for an American Comedy Award, Dom Irrera's stand-up material was honed in a multi-generational Italian household in South Philadelphia with his mother, sister, grandmother, uncles, and cousins, all under one very big roof. A great-grandmother even lived across the street. Together, there were three floors and four generations of family. His first big break was his performance on Rodney Dangerfield's Nothin' Goes Right comedy special for HBO. In 1989, Irrera's own One Night Stand on HBO earned him his first CableACE Award for Best Stand-Up Comedy Special. In 1995, he won a second CableACE Award for the Showtime stand-up series he hosted, Full Frontal Comedy. That same year, he received a second CableACE Award nomination in the writing category for his work on Comedy Central's animated series, Dr. Katz, Professional Therapist. He also starred in a solo stand-up special for HBO in 1992 titled Command Performance. He has performed on The Tonight Show with Jay Leno, Late Show with David Letterman, Late Night with Conan O'Brien, The Daily Show with Jon Stewart, The View, and has made several appearances on The Oprah Winfrey Show. Other credits include a stand-up special titled Comedy Central Presents. 

As an avid sports fan, he hosted four seasons of Comedy Central's irreverent football show Offsides, where he conducted hilarious on the field interviews with football greats. He also hosted Comedy Central's Behind the Scenes at the American Comedy Awards specials in 1998 and 1999. Irrera was a series regular on the 1998 Fox comedy Damon, starring Damon Wayans. His guest star credits include Becker, Everybody Loves Raymond, The King of Queens, and Seinfeld, in which he played an annoying prop comic needling Jerry in the memorable episode. In addition, Irrera voices the character Ernie, the demolitions expert, on Nickelodeon's Hey Arnold! His film work includes a featured role in Hollywood Shuffle, a cameo in The Big Lebowski, The 4th Tenor, and he played himself in The Godson. Irrera has performed at the prestigious Montreal Just for Laughs Comedy Festival and the Cat Laughs Comedy Festival in Kilkenny, Ireland. He's made more appearances at both festivals than any other American comic. He has also performed at the Melbourne International Comedy Festival in Australia and at Edinburgh Festival's Assembly Hall. It was there that he received the Herald Award for Artistic Excellence.