These are what we call the 'YMMV items.' Things that some people find in this work. We call them 'your mileage might vary' because not everyone sees these things in the same way. This starts discussions in the trope lists, a thing we don't want. Please use the discussion page if you'd like to discuss any of these items.
Anticlimax Boss: Compared to the hell you had to go through to get to him, Andor Drakon isn't particularly challenging. Not only is he vulnerable to most disablers, but his melee attacks are surprisingly wimpy and his magic isn't likely to faze anyone who's properly prepared. The biggest worry most players face at this point is the threat of being corrupted to death before they can find and kill him.
Breather Boss: Yulgash, the Master Summoner. He comes a few floors after the battle bunny level and the cat lord, but Yulgash is a Squishy Wizard with miserable melee prospects; his temple is more of a threat than he is. Most players just dash in and hack him apart before he gets a chance to fill the level with monsters.
The Ancient Stone Beast comes a few levels before the Unreal Caves. He has tremendous HP and PV, but terrible DV, average speed, a surprisingly weak ranged attack, and no way of disabling or hindering the player. It's not hard to kite him around the level and chip away at him with blessed projectiles or a phase dagger.
Demonic Spiders: Including literal spiders, who get summoned in hordes and have poison attacks; jackalweres, who summon legions of increasingly-powerful jackals, the greater claw bugs and killer bugs in the Bug Temple, and pretty much everything you meet in the Final Dungeon.
Ghosts can pass through walls and have an aging touch, making them this to any player race with a short lifespan. A "tension room" full of ghosts can easily surround an orc or troll in a corridor and age him to death.
Ogre magi are at least as tough and strong as normal ogres, regenerate their wounds, and can cast invisibility on themselves and ice spells at the player.
Dark elven priestesses, princesses and wizards (called spider factories) are particularly nasty summoners. Not only they summon hordes of spiders, which fill the area with immobilising webs and use poison, but have themselves nasty attacks such as paralyzation and energy ray spells.
Annihilators can destroy any non-artifact item you have equipped if they get within melee range. Thankfully, they aren't particularly resilient or powerful, but if one of them rips apart your amulet of death ray resistance or girdle of carrying, expect things to get ugly fast.
If you ever get a message about 'a deadly and chilling silence', run. Any melee attack in the room gets a massive damage multiplier, turning even the weakest of monsters into fearsome threats capable of splattering end-game characters within a few turns.
Goddamn Bats: Summoners of any kind can quickly become unbearable. Karmic creatures are just as bad, because hitting them causes your character to get cursed and/or doomed, which is a highly undesirable status effect. And also cats. Killing even one of them makes an enemy of a high-level NPC in the end game instead of a very valuable artifact ring.
Good Bad Bug: Let a dragon pick up a pile of gold. Kill the dragon. Notice that it gives you twice as much, every time. Lots of fun with vaults, although you've got to be careful if the dragons have a breath weapon that can melt/dissolve the gold.
If you are a Monk and have a nonhostile creature standing next to you, typing "n" to the "are you sure?" message when you use your circular kick results in the kick going off anyway. Bad, right? Not when you notice that it takes zero turns to execute and only hits hostiles.
The Ancient Chaos Wyrm is the boss of the Tower of Eternal Flames. Not only do you have the Tower's environment to deal with (see below), but the wyrm is an exceptionally powerful opponent. It can breathe fire (although you should be ready for that) and powerful energy rays, as well as attacking with confusion and powerful melee attacks. Furthermore, it's very tough, fast, and can heal itself if you manage to wear it down. Just for more fun, the temple is also full of tough fire elementals, demons, and grues.
Nuurag-Vaarn, the Chaos Archmage. For starters, he's located in the Mana Temple, at the bottom of the Unreal Caves, which are themselves at the bottom of the Caverns of Chaos and have a massive corruption rate. Just getting to him requires you to go through a massively trapped hallway, all while magebane and magedoom eyes are draining your PP. The Archmage himself attacks with powerful ice and shock bolts, death rays, confusion, can drain stats in melee range, and frequently casts darkness and invisibility spells.
Keriax, who you must kill for any advanced ending. Keriax is the Ancient Chaos Wyrm on steroids. He can breathe bolts of all four elements, as well as bolts of corruption, all of which are immensely powerful. In melee range, he has five attacks per turn that poison and drain stats with frightful efficiency. He also has a frighteningly potent confusion attack and significant HP regeneration. If you can't figure out his Weaksauce Weakness, good luck. note Thrown potions of cure poison will incapacitate him for several turns
The cat lord. Unlike most other bosses, he doesn't disable you or have any notable ranged offense; however, he doesn't need fancy tricks like that. He is tremendously fast and nigh-on impossible to escape from once he spots you. Once he gets within melee range, he unleashes flurries of hard-hitting, accurate attacks that always punch through armor. Combine that with his enviable defenses, and you have a truly terrifying foe.
That One Level: The Tower of Eternal Flames is generally considered to be the biggest test of a character's viability. For starters, it deals constant, massive fire damage to both the player and his/her inventory. Protecting yourself requires multiple counts of fire resistance, some of which have to be gained intrinsically. Protecting your inventory is harder; a blessed fireproof blanket will protect your inventory, but not what you're wearing. A blessed ring of ice will cover them both, but it's not 100% guaranteed to work. This is all before we get into the matter of the monsters within, or the chaos dragon waiting in a room full of demons at the top.
The Unreal Caves, a very late-game dungeon. It's a seven level dungeon branch accessed from the near-bottom of the main dungeon, with a ferocious corruption rate and the nastiest monsters in the game inside. At the bottom, you find the Mana Temple, which runs you through a trapped hallway before putting you up against hordes of chaos servants, chaos wizards (which summon more chaos monsters), magebane and magedoom eyes, and Nuurag-Vaarn, one of the nastiest mandatory bosses in the game.
That One Sidequest: Most of them. Even trying to save the little girl's puppy has a time limit and puts the PC through a dungeon with a guaranteed giant ant hill on the second level. Giant ants have sturdy natural armor and they are mean. (Additional fun awaits closer to the bottom of the dungeon.)
Pleasing the cat lord requires you to not kill a single cat until you meet him, generally late in the game. Most cats you meet will be hostile, and it's very easy to accidentally kill one of the weaker ones if you aren't constantly paying attention. If you complete it, you get the Ring of the Master Cat, arguably the best ring in the game. If you fail...
Thrundarr's first quest requires you to kill a random monster. You might get something easy to find like a cave bear or a barbarian, or he might assign you something rare or relatively out-of-depth like a baby dragon or a dark elf lord. Even worse, it's possible for him to assign a cat, which puts you in a very uncomfortable position. To make matters worse, if you screw up Thrundarr's second or fourth quests, you'll get another random monster hunt.
Unwinnable by Insanity: The Pyramid and Minotaur Maze both close up once you reach a certain level (17 for the Pyramid, 31 for the maze). Anything inside is Lost Forever once they close. If you drop one of the Chaos Orbs, leave, and then gain that level, the orb will be irretrievable. However, this is nigh-impossible to do unintentionally.