If there person is on the same plane as me I can hit them fine the first time, but I really struggle with getting a shot off on someone who is in the background.  I usually have to hold down the ammo button and wave the stick around until I see it going in the right area.
 
Do I just suck at the shooting or are you not supposed to be able to drop into a crowded room and get like one-hit style (I mean super accurate when I say that) kills on everyone?

I find it's down to luck mainly.  I can go into a room and clear it in seconds but other times I find it hard to hit a guard at all.  It really depends on where you enter, where they are, and also part luck.  I am getting better the more I play though and finding myself missing a lot less.

Yeah, I have had a few struggles with the aiming system. It is very cool for a sidescroller, but the x, y, z plane sometimes gets wonky when you aim into the background. I have forgone the quest to get the headshot achievement as quickly as possible (it will come with progression instead) and I shoot a guard whenever that laser dot is over them.

I have a problem with shooting the people in the background too. It can be difficult sometimes.