Fitzsimmons has performed his comedy on numerous programs such as The Tonight Show with Jay Leno, Late Show with David Letterman, Late Night with Conan O'Brien, Chelsea Lately and Comedy Central Presents. In 1996, Greg hosted the MTV game show Idiot Savants. He is also a regular commentator on Vh1's Best Week Ever and I Love The series. From 2003 to 2005, he was one of the writers and producers of The Ellen DeGeneres Show for which he won four Daytime Emmys. He went on to write for Louis C.K.'s sitcom Lucky Louie. He is a frequent guest on The Howard Stern Show on Sirius Satellite Radio, Howard 100, and hosts his own show on Howard 101, The Greg Fitzsimmons Show. He also is a frequent guest on The Adam Carolla Podcast. His father was New York City radio personality Bob Fitzsimmons. In 2010, Fitzsimmons appeared on John Oliver's New York Stand Up Show.
Fitzsimmons hosts a weekly podcast which is available on iTunes. It often features the same guests as his radio show, as it is recorded just after his live show ends. His newest book "Dear Mrs. Fitzsimmons" was released on November 9, 2010.