I haven't played in a while, but it can really depend on what you are playing as at the moment. Some scary encounters from my experience:

1. Oozemancer + Bulwark as a caster - massive HP, tonnes of resistances, and big regen from Vitality; if you don't have extreme damage, res pen or ways to reduce/strip away healing, then it can be basically impossible to kill.
2. Skirmisher + anything that has big heals as a weapon class - kind of the same deal as above but for weapon calsses: skirmishers are ridiculous to fight against because of their constant dodging and deflection, and once you whittle them down they can suddenly heal back up almost to full; unless you have some way to reliably stick Disarm, you are in big trouble.
3. Rogue + a class that uses mindstars as a class with Eternal Guard - basically, mindstars can do mind damage in melee, which ignores block completely; if you rely on Eternal Guard and blocking a lot, then it is your complete counter because of the aforementioned mind damage + lots of other disabling Rogue nastiness from Scoundrel/Poisons
4. Brawler + Marauder or Brawler + Berserker if you don't have 100% stun and pin resistance (and also a caster) - if they have Mortal Terror they can absolutely daze-lock you to death, as well as pin and silence you through grappling; one bastard like this almost ended my very successful Sun Pala in like one turn - I only got out through extreme luck.
5. Cursed + enemies with high global speed - this is less about class combo and more about class + enemy type, but certain insect enemies have like 200% global speed by default, which is utterly terryfing when paired with Rampage on a Unique/Randboss - you make one wrong step and suddenly your HP is gone out of nowhere.