Dr. Connors reacts from The Rhino antidote he was previously working on and turns into The Lizard. Realizing this, he runs away but is spotted by his son Billy. The Lizard plots his human conquest and plans to defeat Spider-Man.
At the start of this issue, Aunt May has finally decided to go on a holiday for her health. While Peter escorts her to her train, Doctor Connors is also nearby, waiting to meet with Martha and Billy, his wife and son. However, while he's waiting, he starts to panic as his hand turns green and scaly, just like a lizard's. A moment later he calms down though when his hand turns back to normal. He decides that he was just imagining it in the excitement of waiting for Martha and Billy , yet still has his doubts.
A second later it occurs to Curt Connors what happened: In the last issue, he helped Spider-Man make a potion to defeat Rhino. Since it used similar ingredients to the lizard serum he made years ago, it is possible that simply inhaling its fumes has triggered the transformation into the Lizard.
Meanwhile, on the other side of the station, Billy and Martha have just hopped off their train, and are looking for Curt. His hand is fully changing into a lizard's, so he is panicking again. Unfortunately for Curt, Billy spots him at that moment. Curt decides the smartest thing he can do is to get away from the crowds at the station so that the crowds will be safe should he change to the Lizard. He runs down a train tunnel as people yell at him, thinking he's a fugitive.
Martha realises that the reason Curt must have run away is because he is changing again, and to calm Billy down tells him that it wasn't Curt; that he was mistaken.
Down in the train tracks, the Lizard's tail has returned and his right arm has grown back. His first thought is to find a lair of his own, and so he smashes a tunnel wall with a wooden beam. Walking through the gap, he declares that he is going to start planning the downfall of both Spider-Man and the human race.
Back at the station, Peter says his final goodbyes to Aunt May, before her train leaves. Once the train is gone, Peter thinks to himself how relieved he is that he finally convinced her to leave, as she needs the relaxation. Out of the corner of his eye, Peter spots Martha Connors looking distraught and worried. He changes into his Spider-Man costume then swings down to Martha. Martha sends Billy off so she can talk to Spider-Man about what she fears: that Curt has transformed back to the Lizard. Martha tells Spidey that from what she saw off Curt, he was heading down the train tunnel. Spidey leaves her so that he can go see if he can find Curt.
While exploring the tunnels, Spidey remembers his last fight with the Lizard, and how powerful he was that time. He also recalls how he defeated him: by mixing a potion that could cure him. At that point he finds the wall the Lizard smashed, although as there are so many different ways the Lizard could have gone, Spidey decides to go back to the train station. When he arrives, he tells Martha that he couldn't find a trace of the Lizard and suggests that they go to Curt's lab.
Spidey then spends the next hour searching for the Lizard, but gives up since it's too hard. Changing back to Peter Parker, he heads to the Daily Bugle so he can get money to pay for Aunt May's trip. When he's in J. Jonah Jameson's office, Peter asks if Jonah will give him good money for some pictures of the Lizard. After Jonah yells at Peter and Peter leaves, Frederick Foswell is about to start tailing Peter, but Jonah puts him on another story, occupying him.
Peter heads over to a coffee shop called the Silver Spoon to hang out with Gwen, Harry and Flash. Gwen and Peter are about to go over some work notes for a class he missed out on, but then Mary Jane arrives so Peter spends some time introducing her to everybody. Once he's done introducing, Mary Jane and Peter leave the Silver Spoon.
A bit later, in Central Park, the Lizard appears. He breaks into a jewelery store and frames Spider-Man for the theft. J. Jonah Jameson types up the story about the robbery. By the next morning, Peter has read the story and is shocked at the accusation of the front. He calls up Martha Connors and asks if Curt has contacted her yet. She says he hasn't.
After a day spent not concentrating in class, Peter is swinging around the city again looking for the Lizard. A little bit after midnight he finds him and sets up his automatic camera. Spidey and the Lizard have a fight, but the Lizard has the upper hand as his body is too strong to be hurt. Spidey tries to make the Lizard remember who he is by reminding him of his family, but the Lizard doesn't even listen. Taunting the Lizard so that he'll follow him, Spidey climbs a wall and the Lizard follows after him. A crowd has gathered by this time, and they realise that since Spider-Man isn't the only one who can climb, its possible that the Lizard pulled of the jewelery robbery.
Spidey tries punching the Lizard again, but again it's fruitless. The Lizard manages to knock Spidey off the roof they're fighting on with his tail, and Spidey only survives by shooting out his webbing. The Lizard slithers down the wall as fast as possible, and manages to slice through Spidey's webbing. At the last second Spidey shoots out a "web mattress" to break his fall. Despite the mattress, his arms is still sprained. The Lizard retreats since there's too many people around.
Spidey goes over to visit Martha Connors and confirms that the Lizard is back again. He returns home and is depressed since he can't go out of the house otherwise people will see his sprained arm and guess that he's Spider-Man. At the end of the issue, Peter wonders how he will be able to pull that off, even while the Lizard's at large.