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Anticlimax Boss: If you don't power it up, the Final Boss is kind of a pushover compared to everything else you've fought. You're automatically healed to full health before fighting it, and though it gets a whopping four attacks per round, the individual attacks don't actually deal that much damage. It's also just as vulnerable to status effects as everything else, and doesn't have a whole lot of tricks up its sleeve.
Game Breaker: Vorpal Picks and Void Gems, which cripple enemies' attack stats. There aren't many of them, though, so they usually fall under Too Awesome to Use.
Dison has an ability that halves the maximum health of an enemy. This works on bosses.
Lyla. Full-party healing and powerful attacks? You'll likely never take her out of your party.
That One Level: The Organic Tunnels probably count; it's an extremely large and confusing network of fleshy tunnels that's absolutely full of powerful monsters and locked chests.
The Netherverse Deity can be difficult too, especially on a solo run, since it has a spell that negates any status effects upon it. This is in a game where status effects are vital to success.
Hell's Champion. However, this is mainly due to its flunky, Dante's Companion, which gets three attacks per turn, all of which are pretty painful.
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