In 1990s Lobdell became known for his work 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. He wrote the first 28 issues of Generation X, and at one point was writing both main X-Men titles for a lengthy run. 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. He also had runs with the Excalibur and X-Factor titles.
Scott Lobell was the primary creative force behind most of the major X-title related storylines, especially the major cross-overs, throughout a majority of the 1990s, including "X-Cutioner's Song", "Fatal Attractions", "Phalanx Covenant", "Age of Apocalypse", the "Onslaught" saga, and "Operation: Zero Tolerance". He returned briefly to Marvel in 2001, to try and tie up loose ends he left behind and wrote one last storyline, dubbed "Eve of Destruction".
Many of the concepts and even characters created by Scott Lobdell and fellow X-Men writer Fabian Nicieza were used throughout the run of the popular 1990s X-Men: The Animated Series. Lobdell is even referenced in episode #46 of the show, "One Man's Worth", where he poses as a human used to fuel Trevor Fitzroy's mutant power.