Peter Parker (Tobey Maguire) is a nerdy high school senior in New York City. His parents are dead and he lives with his Uncle Ben (Cliff Robertson) and Aunt May (Rosemary Harris). He has a crush on his next door neighbor, Mary Jane Watson (Kirsten Dunst), who is also one of the few classmates who is nice to him. Her boyfriend, Flash (Joe Manganiello) and his buddies pick on him. Peter's only friend is Harry Osborn (James Franco), who, though rich and good-looking, is similarly an outcast. Harry, however, is somewhat jealous of the affection his father, Norman (Willem Dafoe) shows Peter. Norman, the head of weapons contractor Oscorp, appreciates Peter's scientific aptitude and can barely conceal his desire that Peter was his own son.
Peter's science class takes a field trip to a genetics laboratory at Columbia University. The lab works on spiders and has even managed to create new species of spiders through genetic manipulation and combination. While Peter is taking photographs of Mary Jane for the school newspaper, one of these new spiders lands on his hand and bites him. Peter comes home feeling ill and immediately goes to bed. At the genetic level, the venom injected by the spider bite begins to work strange magic on Peter. Meanwhile, General Slocum (Stanley Anderson) visits Oscorp to see the results of their new super soldier formula. When one of Norman's top scientists, Dr. Stromm (Ron Perkins) warns him that the formula is unstable, General Slocum threatens to pull all of the military's funding from Oscorp. Later that night, Norman exposes himself to the formula. He gains superhuman strength and agility but is driven insane. He kills Stromm and steals two other Oscorp inventions, an exoskeleton and jet glider.
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