After attending the University of North Alabama, Thompson worked as a disc jockey at several stations in the southern United States before meeting his partner Brian Phelps in Birmingham, Alabama in 1986. The next year the duo moved their show to KLOS-FM in Los Angeles, where they remained until the show's end in 2012. Thompson's wife, Lynda, their three children (Matthew, Amy and Katie), his nephew David, and his niece Nina are well-known among regular listeners of the program. Thompson plays drums and is a huge Elvis Presley fan.
On June 13, 2012, Thompson announced that he would be retiring from radio after 25 years and would move to Charlotte, North Carolina with his wife, mentioning that his new home would be equipped with a studio that would allow him to do occasional media work. His last day at KLOS was August 17, 2012. Thompson and his wife now host The Mark & Lynda Podcast, which focuses primarily on relationship issues. In addition, Thompson co-hosts the Pro Football Slam podcast with Los Angeles Times journalist Sam Farmer. He also began hosting the Cool Stories in Music podcast in December 2013. According to Thompson, the podcast is inspired by the biographies, stories, and chart trivia segments of the Kasem-era American Top 40 radio program.
On December 8, 2014 Mark announced on his podcast he would be returning to morning radio in Los Angeles. He will be doing morning drive from his home studio in NC. He also announced that Cool Stories in Music will be syndicated on Sunday on the same radio station.