Born in New York, Gaines grew up with a penchant for puns and practical jokes and a fondness for fantasy radio shows such as The Witches' Tale. He flunked out of Brooklyn's Polytechic Institute during his junior year and joined the Army Air Corps in 1942. After the war, he coedited Picture Stories frp, Science for his father's Educational Comics. He was studying to become a teacher when he inherited EC in 1947. He gradually transformed a line of funny animal titles into crime, romance, and Western books. In 1950 Gaines launched the "New Trend" line - with EC now standing for Entertaining Comics. These new ECs offered science fiction with Weird Fantasty and Weird Science, crime with Crime SuspenStories, and horror/fantasty with The Haunt of Fear, The Vault of Horror, and Tales from the Crypt. Eventually Gaines added Frontline Combat, Two-Fisted Tales, Shock SuspenseStories, Mad, Panic and Piracy. His SF titles adapted the short stories of Ra Bradbury, initially without Bradbury's knowledge or consent, to comic books.

Gaines assembled a gifted editorial staff - Harvy Kurtzman, Al Feldstein, and Johnny Craig - and hired the more talented artist in the field. Unlike most publishers, he was closely involved in the story material, from devising plot premise springboards to proofreading. The result was a runaway success, widely imitated at the time and very influential for years to come. IN 1954 Gaines was caught in the wave of negative publicity generated by investigations into suspected links between comic books and juvinile delinquency, and pressure from parent groups and distributers prompted Gaines to cancel the line. He attempted to rally, first with his "New Direction" comics and then with a group of black-and-white titles. Finally, he concentrated solely on Mad, edited by Feldstein after Kurtzman's departure. Gaines turned it into an impressive success, after converting it from a comic book into a black and white magazine, and there have been endless spinoffs and reprints.