The doc injects himself with the spliced DNA serum, and almost immediately his arm starts to grow back. He gets in a taxi to catch up to his business partner, but headaches aren't the only nasty side-effect, as he starts to transform into a giant lizard.
Meanwhile, Peter is at Gwen's place for the first time to meet her parents, and gets into an argument with her dad, the police chief, about the merits of Spiderman. Outside on the balcony, Peter shares his secret and steals a kiss with his girl, before he is off when he hears sirens.
The Lizard is tearing up cars on a bridge to get to his business partner. Spiderman beats him off, and saves the day by rescuing a boy from a falling car, making a friend with his dad.
Next day, Peter drops by the lab, and grows suspicious of the doc's attitude. Outside he sees a few lizards making their way down to the subway, and hatches a plan.
That night he spins a web in the sewer tunnels, hoping to catch the lizard - and take a pretty picture at the same time. The doc has relocated his lab underground, and ups the dosage hoping that the effects don't wear off. He transforms again, and easily sneaks up on Peter before picking a fight. Spidey swims away to safety, while the lizard is snapped by the camera - and notices a 'Property of Peter Parker' label on it. Like those regular labels you have on all your belongings, especially your undercrackers, as you don't know when you might lose them.
Next day, Peter is back at school when the Lizard strikes again - with an even greater dosage to give him a Godzilla look. They smash up the school, but both manage to escape before the cops show. The lizard heads back to the lab to get the amplification tool, then makes his way to the tallest tower in the city.
Spiderman is tracked by the police and soon cornered. He fights his way free, but not before the captain sees Peter without his mask. Peter begs him to let him finish the fight. As he swings away a cop shoots him in the leg for no real reason.
Spiderman has fallen behind, and needs to reach the tower before the Lizard releases the toxin into the atmosphere. With a little help from his crane buddies he uses the platforms to beat the traffic and swing away.
He gets to the tower just in time. They fight. The captain shows up and shoots the lizard with a shotgun as they freeze him with nitrogen. The nitrogen soon wears off and the captain is gutted by the lizard's claws. Spiderman manages to detoxify the chemicals before they are released and it creates an antedote that heals the doc and the Feds he infected earlier. He starts to fall, but the hybrid doc, now realising the error of his ways, reaches out a hand and helps him up.
As he lies, dying, the captain tells Peter to keep up the fight, and to always wear his mask as he'll make enemies. He then makes the young lad promise to leave Gwen alone, to protect her from harm.
After her father's funeral, Gwen confronts Peter, and finds out for herself why he hasn't been around to comfort her.
Back at school, Peter is late again - and promises to try better. The teacher tells him to not make a promise he can't keep - Peter whispers to Gwen that those are the best types of promises.
After the credits, the doc is taken to a criminal asylum, where he meets his roommate. The man asks if he told Peter what really happened to his father, but the doc begs him to leave him alone … for now.