You mean this ISN'T about Vampire the Masquerade Bloodlines?
Currently, as I'm getting back into the postgame of Etrian Mystery Dungeon: Those fucking owls that hypnotize people and make them start acting weirdly. Nothing sucks more than them throwing away their sword in a way that makes it impossible to pick back up, or they use up a limited use rare item, or they throw away your LAST UNCURSED GO-HOME-ITEM AUGH. Also, the Teleport Traps that isolate one party member in another room, which means they're likely to die horribly unless you can "recall" them somehow with your party. In the "Everyone is level 1 with no items being brought in" dungeons, it can be a run-ender. ;_;
Overwatch: Rolling Hanzo in Mystery Heroes. I suck as him. Like, I suck at playing as Tracer, Genji and Widowmaker too, but I can at LEAST do something with them, even if it's just a little. With Hanzo? All I can do is spray arrows in the general direction of the enemy and PRAY that they hit (and they never fucking do for me). The only really proactive thing I can do is fire Scatter arrows into tunnels when I see the enemy running into one. Bonus points of hatred if I roll Hanzo mutiple times in a row. I have legit lost games of Mystery Heroes because I was having ZERO impact with this chucklehead. Seriously, how do people MAIN this stupid character?!
XCOM 2: Codexes. Goddamn codexes. Unless you have some flashbangs on you. Then they're tolerable. The fucking clone counter ability is beyond frustrating.
Shin Megami Tensai Devil Survivor: Those late-game enemies that have Reflect Physical or Nullify Physical. They're WAY too common and make any physical fighting teams worthless. I'm just fortunate that my main character is an Almighty-focused ubermage every time.
RPGs in General: ANYTHING that has a one-hit-kill attack (I mean "This spell causes the death status, without causing damage" kinds of attacks) that isn't somehow telegraphed. I HATE those with a passion. Oh hey, this enemy just randomly has a 25% chance to just kill you if he rolls this attack, and he happens to move faster than your party! Bonus points if you're playing a game where if the main character dies, everyone dies, because you KNOW that at least once in the game, your main character will get instakilled with no way to prevent it, causing a party wipe. There's a REASON why in my own RPGs, there are not only no instant-death-status-effect-attacks, but many really powerful enemy moves have the enemy glow and telegraph "Hey, I'm gonna hit you with something REALLY powerful that might kill someone in one shot or seriously wreck the whole party, this is your chance to try to stop me!" It gives the player a chance to prepare and strategize, AND it allows these attacks to be quite devastating, as the player now has the opportunity to counter it.
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EDIT:
Semi Tangent: Larp/tabletop Characters who render your own character useless.
Oh hey, I'm a sneaky Nosferatu, time to sneak in the back door and get a bonus strike against one enem- Nevermind, my beefstick mad scientist ally just killed like 4 dudes in the time it took me just to sneak up behind one guy, because Tzimisce are fucking broken. (Oh, and she could out-stealth ME with the "I turn into a puddle of blood" skill. When IM THE GODDAMN INVISIBLE STEALTH CLASS)
Oh hey, I'm a dude who is really well adapted to most situa- oh, nevermind, everyone else in my party is specialized in one of each of the things I can do, meaning I'm mediocre at everything.
Oh hey, I'm a plotty evil nobleman about to cheat a ton of people out of potential inheritance and claim it all for mys- Oh, the lawyer I'm in a debate with has a 5 star rating in Law and I can't use my 4 in resources to bribe him because he has a perk/aspect that makes him unbribe-able, and since I'm not LYING to him, my 4 in subterfuge is worthless? And everything is indicating that this guy will be my main obstacle in this LARP, when he can basically shrug off my two biggest assets? AUGH! (Fortunately, the GM is letting us respec between the first and second games, so I can fix this one)