Spider-Man has (probably) the most personal rogue's gallery, seconded only by Batman.
Green Goblin (Norman Osborn) - Father of his best friend, killer of his first love, man who cloned him and "brought his parents back from the dead", just to mess with him. Knew his secret identity, flaunted it all the time. Kills his clone, who Pete had just reconciled with. Possibly steals his child. Becomes the leader of HAMMER, basically rules the world. May still be alive, running things in a sewer.
Green Goblin (Harr Osborn) - His best friend, knows his identity, fukks with him constantly. Tries to kill both Peter and MJ, before dying (obviously pre-OMD)
Kraven - "Kills" Spider-Man, and buries him. Puts the suit on, because he's crazy, and tries to become Spider-Man. Comes back from the dead, and gets his entire family after Spider-Man.
The Lizard - Peter Parker's teacher and mentor. Becomes a crazy lizard in an attempt to regrow his arm. Dude eats his own kid.
Alistar and Spencer Smythe - Again, a family connection. Both hate Spider-Man so much, they throw their lives away trying to kill him.
Scorpion (Mac Gargan) - Created by JJJ to kill Spider-Man. Goes crazy due to the experimentation on him, fusing animal DNA with a humans. Takes revenge, obviously, by targeting Spider-Man.
Venom (Eddie Brock) - Spurned symbiote finds someone who believes that Spider-Man ruined his life. Turns him into a near unstoppable killing machine, with a sick sense of duty. Knows his secret identity, can bypass his spider sense, has no problem threatening Aunt May and MJ.
Venom (Mac Gargan) - Still pissed off about the whole Scorpion thing, he now gets the Venom Symbiote. Goes nuts, eats hookers, and pretends to be Spider-Man, while on the Dark Avengers team.
Carnage - Offspring of the Venom symbiote, is a murderer with no remorse. Kills everything. Closest thing that Spidey has to the Joker, someone that he should just kill to be done with, as opposed to having him be put in prison, just to escape and kill again.
Dr. Octopus - "Kills" Spider-Man (quotes because who knows if he is going to come back or not) and takes over his body. Gets him fired, burns bridges with MJ, gets his Aunt to loan him everything she has to start a new company that will fail (good old Parker luck). All to prove that he is "Superior" to Spider-Man. Oh, and also almost blew up the world, just to get to this point.
I gotta go with Spidey. Everything about his rogues is personal.