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.

The Crime Lords, led by Silvermane, are holding The Kingpin accountable for his failure to eliminate Spider-Man. So six of the Wall-Crawler's greatest enemies are called together to do the job: Doctor Octopus, Mysterio, The Scorpion, The Rhino, The Shocker and The Chameleon. Unfortunately, Spidey's powers have been on the blink due to the changes in his blood chemistry.

Dr. Mariah Crawford has developed a cure for Spidey's disease, but she's reluctant to give an untested serum to Spider-Man that may result in permanent loss of his powers or worse. But after an angry outburst from Spider-Man, she hands it over. Peter, at the ESU lab, is secretly observed by Michael Morbius, who then swipes the infected blood sample after Peter leaves for the night. Working alone in the campus bell tower with borrowed equipment, Morbius has an accident which will change him forever...

After Spider-Man mutates into the Man-Spider, Dr. Mariah Crawford summons Sergi Kravenoff, better known as Kraven The Hunter, to help her track down Spider-Man and cure him of his mutation with a newly developed antidote. Unfortunately, the Punisher is hot on Spidey's heels. Will the Punisher succeed in destroying Spider-Man in his new mutated form or will Kraven and Dr. Crawford reach him first?

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 that it can cure Spider-Man’s mutagenic transformations with the tablet.

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?

Under the psychiatric care of Dr. Kafka, Eddie Brock has come to believe that Venom is a figment of his imagination. Then Baron Mordo tempts Eddie -- reunification with the alien symbote that makes him as powerful as Venom.

Peter Parker and Mary Jane are finally a couple, but there happiness is short-lived as the Green Goblin, armed with a time distorter and the true identity of Spider-Man, seeks to destroy Spidey, by any means necessary.

When a savage creature begins attacking people in New York, Black Cat tries to convince Spider-Man that he needs her help to stop it. All clues point to the creature being Kraven The Hunter, but sleuthing by Debra Whitman, Flash Thompson, and the Black Cat solves the case. The beast, Calypso, is related to Kraven, but the Hunter wants to capture and cure her.

Deborah Whitman has located Morbius, the Living Vampire, and brings him back to ESU to work on a cure. Just before leaving town, Felicia hears of this and uses the trip as an excuse to stay behind as the Black Cat. Together with Spidey and Whistler, she has to take on Herbert Landon and the Shocker in order to save Morbius from himself.

There's a new Vampire in town, but Morbius is getting all the blame. Just as Spidey, Black Cat, Whistler and Morbius have the Vampire Queen trapped, Blade bursts in and prevents her destruction. His revelation sets the others against him, while the queen attempts to create an army of vampires. Meanwhile, Harry Osborn discovers Peter's spare Spider-Man mask!

Peter and Mary Jane get engaged! The happy couple goes to ask Dr. Connors if he'll give away the bride, not knowing that he's been fighting against the return of the Lizard. While they are talking to him, three more humanoid lizards attack and kidnap Dr. Connors. With the Lizard taking over and Spider-Man captured, Margaret Connors, Mary Jane Watson, and Debra Whitman will have to save the day!

Mary Jane and Peter arrive in Niagara Falls for their postponed honeymoon, but it is soon interrupted when Hydro-Man returns and kidnaps MJ!