The celebration kicked off on Wednesday night with a preview of the San Diego Convention Centre's showroom floor: 460,000 square feet of TV, film and video game displays, along with toys, art and comic books for sale.
What started as a comic-book convention with 300 participants in 1970 has grown into a corporate-heavy media showcase that draws more than 130,000 attendees.
Netflix, Warner Bros., Fox, HBO and Marvel Studios are among the companies hosting large-scale presentations with top-name talent.
But while Hollywood has raised Comic-Con's profile, comic book enthusiasts say it keeps edging out the book buyers and sellers at the heart of the event.
Jamie Newbold, who's been attending Comic-Con since 1972 and selling comic books there for more than 20 years, said that as big entertainment companies have seized on the convention's fan base, the cost of exhibit space on the showroom floor has become prohibitive for small vendors.