Pointlessly over-powered enemies. I've been replaying Fallout3 recently and I have forgotten just how much firepower some enemies take!
The Giant and Albinio radscorpions, Super Mutant Overlords and Feral Ghoul Reavers are the worst culprits. It's fine when you are outside and can use the FatMan at range but at other times you just might as well stuff a Nuka Grenade down your trousers and save them the effort...that or hotkey stimpacks and whack that key like you're playing Daley Thompson's Super Test! The only real defense is to hit them with the Dart Gun (except for the Radscorpions, of course) and run away, trailng a large amount of bottlecap mines!
That was one improvement that FNV had over F3 - enemies / creatures that had a more sensible number of hit-points but could still wreck your shit so it wasn't made too easy. This was a relief because, while in F3 I've been known to rack up over 70 mini-nukes without cheating, I've never found more than 5 in FNV!
Wardy