Hailing from Long Island, New York, Guggenheim worked in Boston as a lawyer and part-time writer for five years. After a romantic comedy script led to a few meetings he decided to make the move west to be a screenwriter. He based the time of this move to coincide with the season that television companies hire new writers. The Practice was his first official job.

He served as an intern at Marvel for a time in 1990 for editor Terry Kavanaugh (Excalibur, Namor, Marvel Comics Presents). He also managed to color an eight page Iceman/Human Torch story while there. His writing experiences also include the comics Aquaman for DC, Wolverine and The Punisher for Marvel, and an undetermined amount of script work for the Rare Game Perfect Dark Zero. He also served as a supervising editor for Law & Order, Jack and Bobby, Miami,and In Justice.

He wrote Blade for twelve issues with artist Howard Chaykin.

In 2006, Guggenheim took over the writing duties for The Flash. Guggenheim's run concluded with the death of the fourth Flash, Bart Allen. It was then revealed that Guggenheim was brought onboard as writer to make way for the return of Wally West as the Flash with Mark Waid to resume writing the title.

At the San Diego Comic-Con in 2007, it was announced that Guggenheim would be one of the rotating team of writers on The Amazing Spider-Man starting in the fall of 2007, following the conclusion of the "One More Day" storyline in the Spider-Man comic books. His first story appeared in Amazing Spider-Man #546.

He also launched a creator-owned comic, Resurrection, for Oni Press.

Guggenheim is still involved in television script writing, and with Greg Berlanti, he is the co-creator of Eli Stone, a television show for ABC which started its second season in the fall of 2008. He wrote the comicbook Young X-Men for Marvel which was launched in April 2008 (it was confirmed in Marvel Previews #65 that Young X-Men ended with issue 12), and has a comic with Hugh Jackman and Virgin Comics, Nowhere Man, in the works. He is currently working on Super Zombies for Dynamite Entertainment and Stephen Kings N.

He wrote the script for the 2009 video game Wolverine, developed by Raven Software, a video game based on the film with the same name.

Guggenheim was intended to take over Action Comics after the War of the Supermen limited series, but has been replaced by Paul Cornell instead Guggenheim will write another project. His other project is in fact writer of Justice Society of America.

Marc is currently an Executive Producer of ABC's No Ordinary Family.