Real-Life Relative: Ted Raimi in all three films; Tobey Maguire's half-brothers (the two boys who give Peter back his mask) in 2; Sam's Raimi's daughter (the little girl with the camera who sells it to JJ) in 3.
What Could Have Been: Alicia Witt, Tara Reid, and Eliza Dushku all auditioned for the role of Mary Jane. Kate Hudson was the initial choice but she turned down the role.
Jake Gyllenhaal would've taken over the role of Peter Parker if Maguire's back problems became too much. Which makes a lot of sense; they resemble each other so much, they actually played brothers in the film of the same name.
The script for the fourth film which caused Raimi to leave. According to reports, it had Peter married to Mary Jane for several years, Adrian Toomes replacing Jameson as head of the Daily Bugle, Spider-Man deliberately killing the Vulture, inciting the wrath of Felicia Hardy -who would here not be the Black Cat, but the Vulture's daughter, with whom Peter would essentially cheat on Mary Jane with; and most notably, the ending would have had Mary Jane leaving with her and Peter's baby, and "Spider-Man No More" happening again.
Sam Raimi also wanted Dr. Curt Connors (who was played by Dylan Baker in the previous two films) to become The Lizard at some point in the film, and the very last scene of the movie was rumored to be a Sequel Hook for Carnage.
Nicolas Cage and John Malkovich were both considered for the role of the Green Goblin.
Stan Lee was going to deliver the "He stole that guy's pizza!" line in 2.
Years ago, James Cameron was going to do the Spider-Man movie with Arnold Schwarzenegger as Dr. Octopus. During this time, there was also another R-rated treatment that had a villain who was a composite character of Norman Osborn and Electro, would feature Spider-Man killing criminals, and would have MJ and Spidey having sex on a big web while Peter kept his mask on.
Doctor Octopus was going to appear in the first film as a secondary villain to the Green Goblin. Raimi felt that having three origin stories would make the movie too cluttered and so Doc Ock was saved for the sequel.