He is mostly known for his work throughout the 1990s on Marvel Comics' X-Men-related titles specifically Uncanny X-Men, the main title itself, and the spin-off series that he conceived with artist Chris Bachalo, Generation X. Generation X focused on a number of young mutant students who attempted to become superheroes in their own right at a separate school with the guidance of veteran X-related characters Banshee and Emma Frost.

Lobdell also had writing stints on Marvel's Fantastic Four, Alpha Flight, and The Adventures of Cyclops and Phoenix mini-series with artist Gene Ha. He wrote the script to Stan Lee's Mosaic and an upcoming film from POW Entertainment featuring Ringo Starr. He also participated in the Marvel Comics and Image Comics (from Jim Lee's WildStorm) crossover mini-series WildC.A.T.s/X-Men.

As of August 2008, Lobdell is the regular writer for Galaxy Quest, a series published by IDW Publishing, with art by Ilias Kyriazis, centred on the eve of the re-launch of the Galaxy Quest series, now titled Galaxy Quest: The Journey Continues.

To date, he has written the majority of the The Hardy Boys Graphic Novel series by Papercutz.

Lobdell has also performed as a stand up comedian and is reportedly good friends with Gilbert Gottfried.

Lobdell is referenced in The Animated Series episode #46, "One Man's Worth", where he poses as a human used to fuel Trevor Fitzroy's mutant power to travel through time. The scene shows Master Mold saying "Lobdell, I have a job for you" he is then grabbed by Fitzroy who absorbs his life energy and creates a time portal. Lobdell created Paranormal Activity: The Search for Katie with art from Mark Badger it was released in December 2009 on iPhone.

His work has won him a good deal of recognition in the comic books industry, including a nomination for the Comics Buyer's Guide Award for "Favorite Writer" in 1997.