Peter Parker and his college science professor Dr. Connors explore limb regeneration. But while experimenting on himself, Dr. Connors accidentally becomes the Lizard, a half-man, half-reptile monstrosity that terrorizes Manhattan.

In order to pay off his debt to the Kingpin, Norman Osborn, a multi-millionaire industrialist, hires a robotics engineer, to design a powerful robot called a Spider Slayer to capture and destroy Spider-Man.

The Kingpin coerces Alistair Smythe, Spencer's brilliant son, to extend the limits of his father's technology and build a line of robotic Spider Slayers to finally capture and destroy Spider-Man.

Doctor Octopus kidnaps heiress Felicia Hardy, and holds her for a ransom that will make up for the humiliation he's suffered at the hands of the Hardy Foundation. J. Jonah Jameson becomes a captive too and it's up to Spider-Man to free them both.

Mysterio, master of illusion and special effects, masquerades as Spider-Man while committing crimes to convince J. Jonah Jameson and the public that Spidey's gone bad.

Daily Bugle publisher and media magnate, J. Jonah Jameson hires Dr. Farley Stillwell, who has developed a new form of genetic engineering to create a super-hero who will capture and unmask Spider-Man.