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.

The six supervillains can't believe their eyes when Spider-Man walks into their trap at the warehouse. But it's obvious why, when they easily overcome and unmask the fraud. Meanwhile, Silvermane and the Crime Lords grow more disenchanted with the Kingpin and want to put him out of business. However, Kingpin beats them to the punch, kidnapping Silvermane.

Mary Jane is being stalked by her former boyfriend, Morris Bench, who's undergone an accidental metamorphosis and become Hydro-Man. Sweeping Mary Jane off her feet in a wave of water, he insists she will love him. Spider-Man, with the help of Mary Jane, must put a stop to the semi-liquid villain.

Spider-Man's progressing neogenic mutation is making him ill and he seeks the aid of a man known to help all mutants, Dr. Charles Xavier. In doing so he meets the X-Men, but is disappointed to learn that Xavier does not 'cure' mutancy, only helps those born that way to accept and control their abilities. In the process of this endeavor he becomes involved in a plot to destroy mutants everywhere, and must stop this hideous plan with the help of the X-Men.

Wolverine catches up with Spider-Man, hot on the trail of the missing Hank McCoy. Discovering his location and the plot to destroy all mutantkind the two team up and rescue Beast in the nick of time just as he was about to become the first test subject of Landon's horrendous plan. But when Landon accidentally falls victim to his own experiment he is changed into a giant monster that feeds on electrical energy.

Dr. Mariah Crawford has developed a cure for Spider-Man's disease, but she is reluctant to give an untested serum to him that may result in permanent loss of his powers or worse. After an angry outburst from Spider-Man, however, 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.

The Punisher comes to New York to deal with the mutating Spider-Man, who has just grown four extra arms, and is in search for also mutated Morbius who is killing innocent people, and the people of New York blame Spider-Man for all that is happening.

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 Spider-Man's heels.

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

Morbius attempts to use the Neogenic Recombinator to turn everyone else into a vampire. Spider-Man and Blade try to stop him, and Morbius' mutation worsens. Morbius kidnaps Felicia Hardy in order to transform her into a vampire.

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.

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.

Spider-Man seeks Curt Connors' aid to help reverse the aging effects of the Vulture's talons. Meanwhile, the Vulture sporadically turns into the man-spider from the mutagenics he absorbed with Spider-Man's youth. At the same time, the Scorpion grabs Dr. Farley Stillwell to seek a cure for his own mutation, while Connors is feeling the onset of his reptilian transformation.