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.

Robbie has set Peter up with a job interview with a researcher by the name of Dr. Mariah Crawford. However, when he gets to her lab, he finds her under attack by a monstrous man who deems himself Kraven the Hunter. Spider-Man leads Crawford away from Kraven to the roofs. There, Crawford tells Spider-Man that Kraven was not always that way, that in fact she loved him as Sergei Kravenoff. Crawford tells of an accident years back that would have killed Sergei had she not used a dangerous potion that saved his life and gave him the strength and instinct of an animal, but turned him mad. Meanwhile, while looking for Crawford at her apartment, Kraven learns of her connection to Robbie and kidnaps him. He then threatens to kill Robbie if Spider-Man does not come to him with Crawford.

The Kingpin is furious at Spider-Man and sends the Shocker and the Rhino out to finish him off with the aid of another new invention of Alistair Smythe. Meanwhile, Eddie Brock, as the symbiote creature Venom, is busy playing cat and mouse with Spider-Man, intruding on Peter's private life and making it clear he knows the web-slinger's secret identity. To make matters worse, Peter soon realizes that the pumped-up Eddie as Venom is stronger than he is.

The vampire hunter Blade arrives in New York to destroy Morbius, but Spider-Man wants to revert Morbius back into his human form.

Dr. Curt Connors is set to study the Tablet of Time, a recently discovered ancient artifact that is said to restore a person's youth. Dr. Connors believes he can cure Spider-Man's mutagenic transformations with the tablet.

With the Tablet of Time, Silvermane's youth is restored, but he continues to grow younger until he finally becomes an infant.

Peter discovers that Mary-Jane is working with a mysterious cult. Baron Mordo, head of the cult, wants them to steal the Wand of Watoom to free his master, Dormammu. When Mordo manages to get his hands on the wand, Spider-Man must team up with Doctor Strange and his sidekick Wong to stop them.

Tired of Jameson giving Spider-Man the rap for all the crime in New York, Peter decides to give up the superhero business once and for all. However, his biggest fan, a little girl named Tyina, is determined to make Spider-Man change his mind.

While a gang of jet-pack wearing thieves run by Jackson Weele, an ex-pilot in a rampaging gyro-wheel, plunder the city, Peter tries to deal with his alter-ego giving him competition with Felicia Hardy. Meanwhile, a good kid with a criminal record, Robert Farrell, tries to help his ailing mother by using his science-savvy and the gang's technology to arm himself as the Rocket Racer. While Spider-Man's fighting crime, the mysterious "Jason Phillips" starts to make moves on Felicia.

Peter is framed for a crime he didn't commit and it's up to blind lawyer Matt Murdock to prove his innocence, who is also known as the Man Without Fear, Daredevil.

Spider-Man and Daredevil manage to recover the disk that can clear Peter Parker's name. However, when Matt Murdock hands the disk over to the FBI, detective Terry Lee discovers agent Choi may not be working for the right side when she hands it over to Richard Fisk. After learning that Aunt May is in the hospital, Peter risks his life to go visit her, but he and Mary Jane are kidnapped when the Chameleon disguises himself as Anna Watson. With Peter and the disk in the hands of the Kingpin, Daredevil must stop the criminal mastermind and clear Peter's name.

Worried that the 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 the Kingpin. When Spider-Man arrives, he discovers Smythe has been turned into a spider-slaying cyborg. 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, after he discovers Mary Jane, the woman he loves, and Harry, his best friend, are engaged.

When Dr. Ohn's Time Dilation Accelerator falls into the wrong hands, all the criminal minds of the city vie for the portal technology. Peter and Mary Jane are celebrating Felicia Hardy's engagement to Jason Macendale when they overhear plans for a major heist.

Harry Osborn is haunted by dreams of his father, the Green Goblin, and Spider-Man. The Goblin visits him and guides him to the Goblin formula and weapons. Meanwhile, the Punisher promises Anna Watson that he will find Mary Jane, and on top of his list of suspects is Peter Parker.

Dr. Doom reverts the Thing to his human form and holds the other heroes prisoner. In an attempt to free his friends, the Thing tells Dr. Doom about the Beyonder. Dr. Doom then steals the Beyonder's powers, but they begin manifesting themselves in the form of creatures from Dr. Doom's dreams.

Spider-Man finds himself in yet another dimension, where he meets himself.