One is that the skills math and the combat maths are not the same. This gets worse as levels grow, and the gaps get bigger. It shows up in stat blocks for monsters and NPCs with weak skill bonuses; in the fact that using skills against defences is not mathematically smooth; etc.
The second is related: there is no smooth interface between the concrete elements of combat resolution (turn-by-turn resolution in a tight ingame time frame; plus tight tracking of physical location using squares-per-turn movement rates) and the abstraction of skill challenge resolution.