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The game was divided into four acts, meeting various villains, including Kingpin, Doctor Octopus, Electro, Lizard, Scorpion, Sandman, Green Goblin, Hobgoblin, and finally Doctor Doom.
Spider-Man battles various villains throughout the game - Beetle, Lizard, Mysterio, Alistair Smythe, Green Goblin, Scorpion, Venom, Doctor Octopus, and Carnage.
After the death of Peter Parker at the climax of the "Dying Wish" storyline in Amazing Spider-Man #700, Doctor Octopus has implanted his mind into Peter Parker's body, determined to prove himself the "Superior" Spider-Man by being both a better superhero and person than Parker ever could be.
However due to Superior Spider-Man (identical to Doctor Octopus scheme in "Dying Wish") having already done this, he has equipped his head with armoured plating.