Okay, so the movie opens with Peter explaining what has happened since SM3. He and MJ aren't dating anymore, but are still friends, and she is in LA shooting a movie. He and Gwen have become good friends, but are not yet dating or anything. He says that forgiveness did not come easily to them, but they eventually forgave him and that he will never forget the mistakes that he made. He is now a staff photographer for the Bugle, but is still living in his same apartment.
In the beginning, Dr. Connors and Peter talk after class and Connors tells Peter of his idea of using Lizard DNA to regrow his arm. Peter says to be careful. On his way home, someone pushes Peter into the street in front of a car. Peter looks but doesn't see anyone he knows, so he figures it must have been an accident and forgets it. Cut to an mansion somewhere, with Kraven the hunter walking around his trophy room, with the heads of every big game animal around. He stops in front of a painting of his parents, and says that he will do his best to live up to their legacy, and that he will go after the Spider-man.
The next day, Peter is driving (on a new motorcycle, not his old scooter), to pick up Gwen to go a museum for a class assignment. He goes to her house, and Captain Stacy answers the door. He mentions that Kraven has come to hunt Spider-man, and that he thinks it is odd. Peter agrees. Stacy says that he wishes he knew more about Spider-man, because he seems to be a good fellow. Gwen comes down and they leave to go to the museum.
Cut to Dr. Connors in his lab, finishing his serum and he tells his secretary to go on her lunch break. He takes the serum, and in a fantastic transformation becomes the Lizard, who is happy to be free, and climbs down the building and proceeds into the sewer.
Cut to Peter and Gwen at the museum, where they are admiring an exhibit on holographic technology. Suddenly Peter sees Norman Osborn standing across the room. He runs towards him to say something, but suddenly he is gone. Peter stands dumbfounded, but Gwen pulls him out of it and they go on with their day. He takes her home, where Captain Stacy and Peter talk a bit about Spider-man, and Stacy tells Peter that he is happy that his daughter is friends with someone so smart. He tells Peter about a break in at Dr. Connors lab, and that Dr. Connors is missing. Peter goes (as Spider-man) to the lab, and looks over the notes and formulas that he finds, and figures out what happens. He is considering places to look for Connors when Kraven jumps in. They fight, Kraven puts up a decent fight but is really no trouble for Spider-man. Spidey knocks him out, and leaves. As he is swinging through the city, something cuts his web and makes him fall, but he catches himself and goes on.
The next day at the Bugle, Jameson explains that he has been seeing a fantastic psychiatrist, and that he no longer hates Spider-man. He is almost friendly, which makes everyone nervous. Comedic scenes ensue here, until Spider-man notices Doctor Octupus crawling along a building across the street. He makes an excuse and rushes out, gets in costume and goes for Ock. Spidey approaches and asks Octavius what he is doing, but Ock just grins and starts attacking Spider-man. They are fighting on a rooftop and the cops show up below, wanting to shoot Ock but not wanting to risk hitting Spidey. Spidey finally gets a perfect shot at Ock's face, but somehow misses and hits a stone gargoyle, which falls towards a young boy until Captain Stacy pushes the boy out of the way and gets hit. Spider-man rushes to Stacy to help him, and carries him to the hospital. On the way, Stacy says "Be good to her, Peter". Stacy is dies on the way. Spider-man searches for Octupus all night, but cannot find him anywhere.
Gwen is crushed by this and hates Spider-man. Peter is afraid of the same thing happening that happened to Harry, so does everything he can to be good to her. They end up kissing and realizing they love each other.
Kraven in the meantime is distraught by the fact that he didn't stand a chance against Spider-man. He is wandering the city, when he ends up on a bridge by a river. He is contemplating suicide when he notices a huge Lizard in a drainpipe. He goes to investigate and discovers the Lizard. He escapes the Lizard but decides to go public with his encounter and hunt him.
Peter is torn between consoling Gwen and finding Connors. It has now been over a week since anyone has seen him, and so Peter goes looking. It is then that he notices Kraven's proclamation to hunt the Lizard, and so realizes he must find Lizard first. While swinging, the Green Goblin soars in on his glider and attacks. They fight in midair for a while, until the Goblin suggests they check out the George Washington bridge. On top of the bridge is Gwen Stacy, exactly as MJ was in the first movie. Spider-man rushes to her and picks her up, she's still alive. Suddenly the Goblin rushes in and knocks her out of his arms, she falls, he webs her and pulls her up but she's dead. Spider-man screams but the Goblin is nowhere to be seen. Gwen is put to buried, and the city once again hates Spider-man. Even Jameson hates Spider-man again, claiming that his psychiatrist was a crackpot. Peter is torn apart, decides to look for Connors to keep his mind of off everything. He finally gets a lead and is on his way to the sewers, when Venom jumps out of some shadows and attacks him. Peter freaks out and they fight, but then again suddenly Venom turns a corner and disappears. Is Peter losing his mind?
Cut to the Lizard working in a crude laboratory in the sewer, but having constant flashes where Connors is in control. The Lizard is wishes to mutate all Lizards into beings like him, but Connors just wishes to himself and the Lizard. Kraven shows up and seriously wounds the Lizard, but cannot finish the job and is forced to retreat.
Peter is at the Bugle, paranoid and jumping at every sound. He asks Jameson the name of his old psychiatrist, and decides to go visit him. He goes to the doctor's house and knocks, but the door suddenly opens and someone tells him to go inside. He goes in and looks around, and suddenly is in a room with Norman Osborne, Otto Octavius, and Eddie Brock. he asks how they are alive, but suddenly they grow larger and larger, until he his tiny. They chase him around the house, which is gigantic also, until suddenly everything is normal and Peter is curled on the floor in tears. The doctor walks in and introduces himself as Quentin Beck, and explains that he was a special effects man on a movie set that was filming near the construction site where he fought the giant sandman and venom. He explains that the battle ruined the movie set, and lost him his job, but during the battle Beck zoomed in with a camera and saw Spider-man's face, and then just looked him up. He has been using a mixture of holographic technology and advanced animatronics to recreate old villians. Peter is in shock from seeing Osborne, Octavius, and Brock. It is at this moment that we see just how unstable he is, as we see him laying in the fetal position hugging himself on the ground and crying/laughing, and we don't know if he understands Beck or not. Beck says that he wishes to destroy Peter and everything he loves, and starts laughing insanely. Peter snaps out of it, realizes that Beck is crazy, and punches him, but the punch goes straight through. It was just a hologram, and Peter sees Beck in another room down the hall. He goes after him, but it is another hologram. Finally he keeps chasing him down until he decides to just tear down the walls looking for him, which he finally does. Peter doesn't want to really hurt Beck, just subdue him and call the police, so he jams a fishbowl over Beck's head and wraps him up in a curtain.
Peter, now no longer fearing insanity, decides to finally find Connors. He tracks the Lizard in the sewer, and finds him nursing wounds caused by Kraven. He tries to help but the internal struggle between Lizard and Connors has made him crazy with rage. He begins tearing into Spider-Man.
Cut to Kraven, who is apologizing to the painting of his parents. He then injects himself with something, and he bulks up, puts his father's lionskin vest on, and storms through a wall, then tears off a manhole cover and dives into the sewer. Meanwhile Spider-man is struggling to keep control of the battle. The lizard finally jumps on top of Spider-man and is about to bite his face, when Kraven shows up and knocks him off. Kraven (in an maddening rage) exclaims how convenient it is that his two prey are together. He lights into the Lizard, but Spider-man pulls him off and throws him aside. This act of kindness awakens Connors enough to control the Lizard to knock out Kraven and to tell Peter about the antidote. Peter takes Kraven topside and leaves him in an alley, then makes his way to Connors's lab. He finds the antidote, and goes back to the sewer, where the Lizard has completely taken control and fights Spider-man throughout the sewer. Spidey drops the antidote into a huge water resevior, and dives in after it. The Lizard follows and they fight underwater until Spidey finds it and injects it into the Lizard, which returns him to Connors. Spidey returns Connors to his family, then goes to find Kraven at his mansion. He shows up, but Kraven won't talk to him. Finally Spidey leaves. We then see Kraven looking sad at the painting of this parents, and he then commits suicide.
Cut to Peter at the graveyard, now at Gwen Stacy's grave, and we here the voiceover about how people he knows are never safe. He goes on to say that no matter how hard it gets, we cannot give into the temptation of insanity, even though the insane is sometimes far easier to live with than reality. The movie ends with Peter in his apartment looking at a photo album, when there is a knock at the door. It is Mary Jane.
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