Norman Osborn hires Spencer Smythe to design a machine capable of destroying Spider-Man - the Black Widow Spider Slayer. But when Flash Thompson puts on a Spider-Man costume as a party gag, the deadly machine spots him, and he's carried off in Peter's place.
Dr. John Watson resumes his medical career as the head of a clinic dedicated to treating rare disorders six months after the death of his friend and partner, Sherlock Holmes, at the hands of Moriarty.
Peter Parker and his college science professor Dr. Curt Conners explore neogenics as a method of limb regeneration. But while experimenting on himself, Connors accidentally becomes the Lizard, a half-man, half-reptile monstrosity that terrorizes Manhattan and subsequently kidnaps his own wife. Spider-Man's task is doubly difficult because he doesn't want to hurt the good friend he knows is trapped inside...but he must stop the inhuman beast who is out of control.
An anonymous tip to the LAPD sparks an unusual multiple-victim kidnapping investigation, forcing the team to rely on board games and puzzles to track down their suspect.