During his patrol, Spider-Man stops a group of thieves who are breaking into a bakery. Simultaneously, Spider-Man takes pictures to give to the Daily Bugle. He happily leaves and makes it back home in times for his curfew, but discovers after developing his photos that he has messed them up. Meanwhile Dr. Curt Connors injects himself with lizard serum to aid the regrowth of his arm. When he awakes, his arm has regrown, but knowing that he experimented on himself, his wife, Martha, is furious.
Spider-Man fights the Lizard at Bronx Zoo.
At school, Peter is attacked with water balloons by Flash Thompson and his sidekick Kenny Kong, which he dodges until he realizes it might reveal his secret identity as Spider-Man. Gwen steps in and gets everyone to laugh at Flash instead. Gwen and Peter go to the Connors lab and help Eddie clean up from a previous battle with Electro. Martha announces that Curt's arm had grown back and they celebrate until they realize scales are growing on his arm, determining that the reptilian half of his brain his taking over. Peter tries to comfort the Connors's son, Billy, but gets interrupted when Curt transforms into a hulking, humanoid lizard and runs off.
While Eddie goes in pursuit, Peter manages to slip out and goes after Connors as Spider-Man. While trying to communicate with him, they end up on a subway train fighting both inside, outside, and underneath it. Finally, Spider-Man falls off the train and Connors escapes. Spider-Man returns to the lab and is given a gene cleanser from Martha which must be administered to Connors orally. He then goes off to Bronx Zoo, where Connors is reportedly at.
Spider-Man enters the lizard room where Connors has taken refuge. Connors knocks him out and Eddie arrives to help him out. When he regains consciousness, Spider-Man comes up with a plan to trick him into the Polar Bear pond. They almost succeed when Connors is alerted by Spider-Man's cellphone ringing. Billy then arrives and tries to talk some sense into his father, but it is useless and Spider-Man leaps in to get Connors into the pond. Spider-Man pours the cleanser into the mouth of Connors who, as a result, returns to normal, his arm lost once more.
The next day, Peter gets the Lizard photos published in the Bugle and gets the money he needs. However, when Gwen, Eddie, and the Connors find out, they are outraged that he ran off simply to take pictures and say he has lost their trust. Although Martha understands the difficult choices that Peter had, she fires him. He secretly grabs another vial of gene cleanser and returns home, frustrated about his reputation. Blaming the events that gave him his powers, he is about to take the vial when he sees a photo of himself with Ben. Realizing that he had saved Curt either way, he decides that Spider-Man is needed and hides the vial under his desk.