I'm rewatching the first season of Agents of SHIELD and it definitely makes a difference when you know where the show is going. Plus I can hear Bear McCreary's theme at the end instead of ABC promos. Spoilers if you haven't watched (but then why are you reading this anyway?).
Ward in particular comes across differently when you know he's playing everyone. The same applies to May, who's Fury's spy on the team. Though I like Skye, she really was kind of annoying in the beginning.
I just finished watching the fourth episode "Eye Spy" and I had forgotten what the objective of the unknown bad guys was - to get a look at this. If I remember correctly when this episode first aired people were more focused on the vertical writing on the right than the rest of what's on the board.