Spader has been a pretty versatile and prolific actor, and his performance in Sex, Lies & Videotape was IMHO his best.
But his signature role is Steff in Pretty In Pink. He embodied that character so well that it was hard not to think of him as a smarmy a$$ in other subsequent roles, despite his character being completely different.
To me, that means that role is a defining one in his career, even if it did unfortunately typecast him for a bit (in reality or in viewer's perceptions).
Man that's a tough one. When we were both younger I think there was similarity face-wise between he and I so I've always had a connection to him. I don't think I could nail one down. Maybe Mannequin. Pretty in Pink would be up there.