So, now that The Dark Knight has set a new standard on what a superhero movie can be, and since Spider-Man 3 is widely considered the weakest installment in the franchise, what are Sam Raimi and Tobey Maguire going to do next?
I genuinely hope they make Peter Parker grow up. He can be a freelance photographer in the comic books for decades, but in the movies, he needs a more natural progression. I think the best way to get Peter to grow up is to have Mary Jane get killed in Spider-Man 4. I say that selfishly because I think Bryce Dallas Howard's Gwen would be a better romantic pairing than Kirsten Dunst's increasingly mopey MJ. They could also have him start out at the beginning of SM4 actually affected by the death of Harry.
If I were doing it, I'd write a treatment that has introduces a cousin Osbourn that gets all of Harry's stuff, and one of his business prospects is the movie industry, and a disgruntled employee there is Quentin Beck, who becomes Mysterio. He then tries to make a name for himself going after Spider-Man.
Meanwhile Dr. Connors finally does his regeneration experiement which turns him into the Lizard. Spidey thwarts the Lizard, and now he has two foes after him, but Lizard's more destructive ways get in the way of an elaborate scheme Mysterio had set up, so they hate each other too. Peter eventually finds a cure for Dr. Connors, and he's restored to normalcy while Spidey and Mysterio have a showdown. Mysterio has kidnapped MJ but winds up accidentally killing her. Spidey goes to a dark place, but Gwen and Connors are there to stop him from murdering Beck. Mysterio is exposed and jailed. Gwen can now be there to pick up the pieces with Peter. Ominous final shot shows the Lizard cure is only temporary.
Spider-Man 5 could go anywhere from there. Sandman, Lizard and Mysterio are all still alive. Hobgoblin could pop up, or Electro, or Chameleon, or any of the other supervillains. Even Kingpin, though he's already been in Daredevil. Or maybe Spidey 5 can have some sort of cross-over with the Avengers or some of the X-Men. Anything's possible in this synergous world. I'd only suggest Carnage if I thought they could do him justice, but I hear they might do a spinoff Venom movie, so Carnage would be the perfect villain for that one.