Green Goblin & The Death of Gwen Stacy
Gwen Stacy was the first girl that Peter Parker ever loved and inThe Amazing Spider-Man #121 she is killed during a fight between Spider-Man and the Green Goblin. It is the Green Goblin's fault that she falls to her death; but there is a wide debate about whether or not Spider-Man's web snapped her neck when he tried to break her fall.
Killing the girl Spider-Man loved wasn't enough, though.
In Spider-Man: A Death in the Family Peter Parker arrives home, after a fight with the Green Goblin, to news footage claiming Spider-Man was the one responsible for Gwen's death. Norman Osborn was, essentially, framing Peter Parker for murder.
The two meet for a fight and, when they both get tired, Peter Parker confesses a dream that he has been having. In his dream, Peter sees a plane crash down and he rushes over to the wreckage. He scours the debris looking for MJ but, instead, he finds Gwen. The fact that Peter only feels comfortable talking to Green Goblin about his dream is a nod to the relationship the two characters have built over the years- and the way the knowledge of a secret identity can change the dynamic between hero and villain.
Also worth mentioning: In The Amazing Spider-Man #512 Norman Osborn gets Gwen Stacy pregnant. She manages to keep it a secret from Peter and give birth to her demon twins in private. I don't know if Peter ever found out about Gwen and Norman- and I wonder how the dream confession scene from "A Death in the Family" would be different if did know.