The New York Post has an article up about Spider-Man 4, which should be releasing at some point after it's finished, which should be within the next two or three years or so. Although there's no confirmation yet on which "villain(s)" Spider-Man might be facing, I have it on good authority that producers are considering the following:
Sub Prime: This terrifying villain lends money to Peter Parker's poor Aunt May. When she can't pay back her loan, he swoops in. Note: This one is causing friction between the producers and the studio, who want to include Sub Prime's evil partner, Bailout, in the story. Producers think two villains is too much.
Centrifuge: He is the duly-elected leader of a Middle Eastern country, trying to get access to nuclear weapons. During an experiment, he's exposed to radiation, and gains the power to weaponize.
Obesity Epidemic: During the Nathan's hot dog eating contest, he accidentally ingests a vat of nuclear waste, and gains the power to eat anything at all. Of course he goes after Mary Jane Watson.
The Rotten Tomatobots: These nasty commenters come out in force whenever their favorite movies receive negative reviews on the Rotten Tomatoes website. When one of them mistakes Peter Parker for Armond White, Spider-Man might never recover.
RIAA Raider: Download anything, and he'll know, attacking with crippling lawsuits. He's doubly powerful because he has the government helping him out (just like Sub Prime, see above). NOTE: Concept art very preliminary.