The Green Goblin
Arguably the premier Spider-Man villain, the Green Goblin has plagued the webslinger throughout his history, cementing his premier status in 1973 by murdering Spider-Man's girlfriend, Gwen Stacy. Norman Osborn, owner of chemical empire OSCORP created the Goblin after going insane from a super soldier serum. To make matters more difficult for Spider-Man, Osborne's son, Harry was Peter Parker's best friend, creating a rift between his superhero and private life. Over the years, there have been several characters who have taken the mantle of the Goblin, including Harry, but Norman Osborn is the best-known identity. He was played by Willem Dafoe in the original "Spider-Man" film with James Franco playing his son, Harry in all three films. The Green Goblin is one of the villains in the Broadway production of "Spider-Man: Turn Off the Dark."
Dr. Octopus
Introduced in July of 1963, Dr. Octopus has gone on to become a major villain in the Spider-Man universe. A nuclear physicist whose tragic radiation accident caused his body to fuse with a six armed apparatus designed for fusion research, Dr. Octopus continues to torment Spidey to the present day. His appearances outside of the comic medium have included cartoons, the feature film "Spider-Man 2" where he was played by Alfred Molina and several video games from 1983's "Questprobe" to a 2010 appearance in "Spider-Man: Shattered Dimensions."
Venom
Perhaps the most popular amongst Spider-Man fans, Venom was created in 1988 by Todd MacFarlane. Using Spider-Man's alien costume, disgraced reporter Eddie Brock became a dark, mirror image of the webslinger, using the knowledge obtained from the alien to discover Spider-Man's secret identity and the location of his loved ones. Like the Green Goblin, Venom has switched identities a few times with Flash Thompson being the current host. Venom was played by Topher Grace in "Spider-Man 3". The character has been seen on various Spider-Man cartoons and video games. His latest appearance in a video game was as a playable character in "Marvel Ultimate Alliance 2."
The Sandman
Since his debut in 1964, the Sandman has morphed between hero and villain almost as much as he can morph into different shapes. A perennial thorn in the side of Spider-Man, he would go on to become one of Spidey's most popular villains, ranking at 72 in IGN's list of greatest comic book villains of all time. He made his film debut in "Spider-Man 3" where his character straddled the thin line between good and evil. A mainstay in Spider-Man based video games, he most recently appeared in "Spider-Man: Shattered Dimensions" where he is a boss in the second level.