Clarke began his acting career in The Hollywood Palace as The King Family Show. He continued to perform with his family on various television specials until the 1980s when he got his first voice acting roles in Snorks and Robotech. He was taught by Michael Bell.

To date, Clarke has voiced over four hundred titles. From 1987 until 1996, Cam Clarke would most notably portray Leonardo, the leader of the Teenage Mutant Ninja Turtles as well as Rocksteady, one of the show's antagonists. Clarke would reprise the role of Leonardo in non-musical spoken portions of the first show of the TMNT: Coming Out of Their Shells concerts designed around the Ninja Turtle characters held at Radio City Music Hall, though the later VHS tape released of the event leaves him uncredited.

Clarke is the nephew to guitarist Alvino Rey and pianist Buddy Cole, cousin to actress Tina Cole, actor and TMNT co-star Pat Fraley, and writer Chris Conkling, half brother to musicians Ric and Lex de Azevedo, and uncle to voice actress Emilie Brown and actress Rachel Coleman.

Clarke is gay,^[1]​ and his experiences inspired his album Inside Out, which changed pronouns in lyrics of classic songs^[2]​^[3]​ and his one-man autobiographical play Stop Me If I Told You This.^[4]​^[5]​

Clarke is a survivor of HIV, having lived with it for decades.^[6]​

• Cam Clarke en Internet Movie Database (en inglés).