Sam Raimi and Tobey maguire aren't signed on (yet), but Sony's set aside May 2011 for its release.
If they're going forward with it, this is what I'd like to see.
It's time for Peter Parker to grow up. Have Harry Osbourn name Mary Jane his heir in his will. Parker moves up in the world with a rich fiancee and now only freelance photographs for fun. Parker gets MJ to use some of her newfound funds to help Dr. Connors with his research. Something goes awry; Connors turns into the Lizard. Meanwhile a second villain pops up. I remember liking Mysterio as a kid, but I couldn't tell you anything about his backstory, but maybe Mysterio kills MJ. Then Parker is seeking revenge on Mysterio while a demented Lizard is seeking revenge on Parker. Meanwhile Gwen is there to be a love interest/damsel-in-distress in third act. I like Bryce Dallas Howard more than Kirsten Dunst anyway. I've liked Dunst in other things, but she's been a wet blanket for three movies now.
Show Parker having grown up and been affected by what's happened in the first three movies. The Osbourns are dead, Dr. Octavius is dead, Eddie Brock is dead. Sandman is still out there. These should take their toll on Peter.
Now the comic relief should continue. J. Jonah Jameson should still be a factor. I don't want Spider-Man to turn into the mope-fest Superman Returns was.
The problem with Mysterio is you can't see his face; also the problem with the Green Goblin. There are other villains where you can but they'd be silly in live-action (Vulture, for instance). If I hadn't seen SM 3, I might have suggested Carnage for SM 4, but since Venom got the short-shift, I'd rather not have them screw up Carnage too.
I also wouldn't mind someone taking over for Sam Raimi. SM 3 was the weakest of the three. I would just hope they could avoid the "Brett Ratner to X-Men 3" drop-off. Get Alfonso Cuaron.