Slott's break came when he became the regular writer for Marvel’s Ren and Stimpy comic. Following its success (it consistently placed in the top 50 best-selling comics) he found himself in high demand to write more children's comics, including DC’s Scooby Doo, Looney Tunes and Powerpuff Girls, but was eager to show a more serious side in superhero comics. After work on Batman Adventures and Justice League Adventures, Slott was given the chance to pitch a series for DC. The resulting miniseries was Living Hell with artist Ryan Sook in 2003. In 2004 he wrote the 4th Parallel storyline for the Justice League which introduced the Red King; this story was published in 2007 in JLA Classified #32-36.
Arkham Asylum's success led to Slott's return to Marvel in 2004 to launch a new She-Hulk series. The title focused on She-Hulk as a "superhuman lawyer" in the Marvel Universe. After relaunching in October 2005, the second series met with higher sales, and after tie-ins with crossover events Civil War and World War Hulk, reached its highest numbers yet. In 2007 Slott left the title with (volume 2) #21, to become one of the writers on Amazing Spider-Man.
While She-Hulk was on hiatus in 2005, Slott penned the Spider-Man/Human Torch miniseries, which chronicled the friendship of the two characters over the years, with each issue paying tribute to a different era of Marvel Comics.
Slott also gave the team the Great Lakes Avengers their first ever solo miniseries in GLA: Misassembled, which featured a character being killed in each issue. He also made the first roster changes to the team since its inception by creating a new character, Grasshopper, and reviving an obscure one, Squirrel Girl. During this period, Slott signed an exclusive contract with Marvel. He has since returned to the GLA twice, first with the 2005 GLX-mas Special, following a name change to the Great Lakes X-Men, and then again in the 2007 Deadpool/GLI Summer Fun Spectacular with co-writer Fabian Nicieza, to coincide with Marvel's Initiative crossover.
At the end of 2005, Slott was assigned to write The Thing's first solo series in 20 years. It was not a sales success, and was canceled with issue #8, despite Slott's attempts to rally readers in a campaign he called "Pull My Thing." The eight issues have been released in a trade paperback entitled Idol of Millions, which sees the Thing and other heroes fighting deadly roller-coasters and other machines in Arcade's Murderworld.
Slott was also the writer of Marvel's The Initiative, which launched following the conclusion of the 2006-7 Civil War storyline. He is also one of the four writers of the thrice-monthly Amazing Spider-Man, a schedule which began in January 2008 following the controversial storyline One More Day. His first three issues placed in the top ten highest selling comics for January, with the first issue taking the number two spot that month, selling around 128,000 copies, a 3% jump from the previous month.
Slott appeared at MarvelFest NYC 2009, where he judged a costume contest with Joe Quesada, Scott Adsit, Chris Claremont, and Frank Tieri.
Slott took over writing duties on Mighty Avengers after writer Brian Michael Bendis's departure, starting with issue #21 and finishing with issue #36. He also wrote Shattered Dimensions, which was published in September 2010. In November, Slott will take over Amazing Spider-Man as the sole writer, marking the book's change to a bi-weekly schedule, beginning with Slott's "Origin of the Species" and "Big Time" storylines, the former of which serves as a finale to the "Brand New Day" series of storylines that began in 2008.