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.

Norman Osborn hires hitman and thief, the Hobgoblin, to take out Osborn's "silent" partner, Wilson Fisk (the Kingpin). When he fails in the attempt, the Hobgoblin changes sides, kidnapping Norman's son, Harry. Harry just happens to be best friends with Peter Parker.

When Aunt May is slightly injured by one of the Hobgoblin's pumpkin bombs during the kidnapping of Harry, Spider-Man enters the fray with a vengeance. After several battles, the trail leads Peter to Oscorp and Harry's own father. For Peter, rescuing his friend is easy compared to explaining to Harry that his own father is involved.

Adrian Toomes wants revenge when Norman Osborn attempts to take over his company, Toomes Aeronautical. He becomes the Vulture and immediately kidnaps Norman's son, Harry. Will Spidey be able to rescue Harry from the Vulture's youth stealing talons?

Spider-Man seeks Curt Connors aid to help reverse the aging effects of the Vulture's talons. The Vulture meanwhile sporadically turns into the man-spider from the mutagenics he absorbed with Spidey's youth. At the same time, the Scorpion grabs Dr. Farley Stillwell to seek a cure for his own mutation. With Doc Connors in the middle, feeling the onset of his own his reptilian transformation, will everyone be cured in time for Peter to meet up with Mary Jane as she confronts her wayward father???

Worried that Kingpin is going to eliminate him after the botched framing of Peter Parker, Alistair Smythe arranges a meeting with Spider-Man to give him information about Kingpin. However, when Spidey arrives, he discovers Smythe has been turned into a cyborg. Part man, part machine, he is now the ultimate spider-slayer! However, when his programming malfunctions, he goes after the man he feels responsible for his father's death...Norman Osborn! Peter must fight a crazed Smythe, as well as his feelings when he discovers Mary Jane, the woman he loves, and Harry, his best friend, are engaged!