Peter Parker e seu professor de ciência da faculdade Dr. Curt Conners explorar os métodos neogênicos de regeneração de membros. Mas ao experimentar em si mesmo, Connors acidentalmente torna-se o Lagarto, um meio-homem, meio-réptil, que aterroriza Manhattan e, posteriormente, sequestra sua própria esposa. A tarefa do Homem-Aranha é duplamente difícil porque ele não quer machucar o bom amigo que ele sabe é preso dentro do monstro... mas ele deve parar a besta desumana que está fora de controle.

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.

With Spencer Smythe dead, his son Alistair turns to the Kingpin to help seek his revenge on Spider-Man and others he deems responsible for his father's death. He captures, Eddie Brock, J. Jonah Jameson, Norman Osborn, and Flash Thompson. He then turns his sights on Spidey and sends three slayers after him. Spidey only manages to hold his ground while fighting them individually. However, he is not so lucky when they combine into a super slayer and carry him off to Smythe.

A space shuttle piloted by J.J.'s son, John Jameson, crash lands on the Tri-Borough Bridge carrying two strange meteors -- One that could provide a new nuclear fuel and one that contains an alien substance. The first is stolen by the Kingpin's henchman, the Rhino, just as Spider-Man arrives to save Jameson and the co-pilots. When the Rhino sends the aircraft off the bridge, Spider-Man emerges from the water with a dark stain covering his costume. Exhausted, he heads for home, only to awaken hanging from a skyscraper, now clothed in a black version of his costume.