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. Mark and Lynda Thompson now host a podcast from their home, with a focus on relationship issues.