Important NPCs are invulnerable, like Oblivion.
You might close off some smaller sidequests, but the folks necessary for the main story (for instance) have a tendency to be "incapacitated" from "killing" blows.
So feel free to go nuts.
Interestingly, NPC allies behave a little different, even if they are non-essential (and thus ripe for killing). When they get reduced to below 0 health, they revert into the "yield " state, which usually means enemy NPCs stop focusing on them to come after you instead. If they get hit while in this state, they will die.
Additionally, you cannot put them into this state - your attacks will directly kill them.