Campbell told Access Hollywood that Spider-Man 4 is set to begin shooting January 2010, and that he's been told by Raimi that he has "a major part. The kicker is that the well-chinned actor knows not what that role might be. Access Hollywood immediately began speculating that he'll be stepping into the villain's shoes, and says fans are touting him for Mysterio. But hey, in our own comments we currently have one vote for Campbell as Mysterio and one for him as Lizard, so I'm going to borrow their investigative technique and say that fan consensus is divided.
As Slashfilm notes, "a major part" could simply mean that Campbell's recurring cameo could throw another kink into Peter Parker's life. As Spidey and Campbell fans know, every time he's appeared in the series he's done something to nudge the superhero into his destiny, and it could be that he does something very drastic to Parker's life. Perhaps he's Mephisto and he'll pull a One More Day, reverse the entire franchise series, and that's how we'll get our reboot.