1. Input locks. it's great that you can fix it easily (alt F12 menu), but I have to go clear them out far too often, just to be able to do basic things (getting locked out while you are switching stages mid burn is super fun).
2: The cameras. The SPH camera is totally fine; but instead of being the same(ish, at least), the VAB camera is this whole other thing where you have to constantly fiddle to keep things centered and get the angle you want.
The in flight camera is mostly fine (at least usually), but when docking it is a nightmare to get the angle and position I want. And on larger craft, using Aim Camera to hop around because I can't move the camera, just to get to the parts I need, is also really annoying.
3. The optimization (as others have mentioned). How I can run AAA games on ultra, yet a decently high part count vessel will stutter and lag (I do understand that this is also a CPU vs GPU thing, too. It's still aggravating, though).
4. The rigid attachment & autostrut system is great for dealing with noodle syndrome, but having to do it to every part individually, every time, is incredibly tedious.
Ok, done yelling at clouds for now.