Cascading alliances. The fact that any opm declaring war on another opm has the potential to drag half of Europe into a war is ridiculous. Just the other day I had one where I declared war on x, who was allied with y, who was allied with z, who was allied with Austria. I died. Where the hell does it end?
Hordes. I hate hordes. They have made some countries basically unplayable (Georgia and Delhi come to mind). Even if you can kill them and occupy every damn province, you have to colonize them, while having to deal with revolts and all of the other bad stuff associated with staying in a war for 50 years while you colonize the GH. This also puts an unnecessary cost in gold and colonists to colonize them. I should have to feel that to play Russia I should turn colonists to free and 400 size just so I kill the GH quicker. It also makes Russia's free cores useless.. The automatic war if your borders touch, the penalty on provinces bordering them.
Defender of the Faith. (Or rather how the AI uses it). Defender of the Faith makes it so Castille (usually) will get involved in Turkey or Russia and will end up taking provinces for hug amounts of infamy, and ruin their economy as they end up getting these random enclaves around the map that they then have to protect (which I think most players would not do). So you end up getting Castille involved in wars all of the place, then you could this with cascading alliances, you makes Orthodox and Muslim nations have a much harder job than they should.
Tech groups. I understand that non European countries had to modernize, but the difference are to much in many cases. You combine that with the inability of the ai, and you end up getting Poland, being helplessly far behind their German neighbors for basically no reason. Then because the Latin tech group starts with OPMs that are protected by the HRE and France, they end up getting the neighbor bonus, as the opms tech so fast. While the other tech groups, their small countries will die. The ai is also completely unable to westernize, I don't think I have ever seen them do it. The way the tech groups are set up, also keep Muslim nations, and the Ottomans in particular way to far behind, and much weaker than they should be historically. Come 1600, any latin group country with more than 1 province can basically go to war with any muslim ai nation and win.