After graduating high school in Los Angeles and acting in commercials, daytime serials, and school plays, Masterson briefly attended college. He later moved to Chicago to begin pursuing an acting career. After bartending and working odd jobs for nine months, he was hired by The Second City, where he worked on stage with Mike Myers, Steve Carell and Bonnie Hunt. Upon returning to LA, Masterson started working with Ryan Stiles and Drew Carey, performing live improvisational comedy as a part of "The Improv All Stars".
Masterson created and co-wrote the web show "Home Purchasing Club" (HPC) for VH1/Spike, which ran for two seasons and featured Kristen Wiig, Jeff Garlin, Diedrich Bader, and David Keochner. HPC was directed by Brian K. Roberts and Executive Produced by Jordan Levin, Pete Aronson and Generate.
Masterson created, wrote and directed "Republicrats" for MSN (Microsoft), portraying a former Fresno TV weatherman who decides to run for President of the United States against John McCain and Barack Obama. Republicrats was reviewed by The Wall Street Journal, The Hollywood Reporter and TV Week as a Top Web Show of 2008. Republicrats was produced by Ivana Ma and Generate.
Masterson has teamed up with Ryan Stiles to write and produce a half-hour comedy pilot called "Memory Lanes", directed by Brian K. Roberts and produced by Masterson, Styles, and Richard Elwood.