Fruit Fucker Prime is ultimately defeated with a button-based minigame.
Charles in the second episode has 10000 HP, but he goes down in 3 hits. You alternate between attacking him and searching a room as Tycho.
SISSY BOSS FIGHT!
In Episode 3, the Leviathan is this the first time you fight it, though the level in question has several worthy boss encounters to make up for that. Both Blood and the Leviathan are this in the fake ending, while in the real one they're fairly strong.
Lampshaded in the 8-bit level in the bank when the party comes to a bridge. The party is attacked by a group of weak goblins, which at this point you can probably kill with a single area attack. Tycho immediately complains about them ruining his expectations of an epic battle, and is quite insistent that what he got was not hardcore enough.
In Episode 4, the bosses in the The Very Definitely Final Dungeon are not only weaker than the Bonus Bosses in the last one, but actually weaker than the normal bosses in most cases. Even the final boss grants a new ability which renders your party near-unbeatable.
Breather Level: Episode 3 has the Star Trek-style level, a fairly quick and easy level coming off the heels of the previous level, which is done in the style of previous Zeboyd games and almost unspeakably difficult.
Ensemble Darkhorse: The Dude on a Walrus has been described by the developers of Episode 3 as the most popular enemy sprite by far. This says something, as there is only one encounter where the duo features in the entire game.
In Episode 3, give Moira the Tube Samurai pin, the Cordwainer pin, and a Self-Help book or max speed boost accessory. This turns Moira into a Lightning Bruiser that gets an attack boost from one class, two speed boosts from both plus the accessory boost, and a skill which translates speed into attack damage. Factor in the fact that Moira is naturally fast and she becomes a monster.
In the Lair of the Seamstress DLC, you're brought down to level 1 and forced to fight enemies of escalating difficulty, with each encounter earning you a couple levels so you'll be strong enough to fight the next one. In theory, this would make every encounter, more or less, equally difficult. What this does not account for, however, is the effect of items, which aren't governed by your level. If you've paid to upgrade the Nihilator, which unlocks after you've bought everything else, half of the encounters can be beaten simply by spamming it. The increasing difficulty will eventually render this strategy ineffective, but by that point you'll be much stronger and able to put up a decent fight against the remaining encounters. The next DLC sidesteps the issue by removing every item except potions.
In Episode 4, Vendoor. Not only does he break the normal item economy by chugging out potions that are better than the ones you use normally, but at level 30 he gets a Heavy Attack that's damage is based on the amount of gold you have. By the time you get this you'll typically be in the final dungeon, where all that gold from encounters and chests just starts piling up. The average attack will do around 20,000 damage, which is about a fifth of the final boss' health.
In the final boss battle of Episode 4, your entire party is granted the use of Tycho's skillset. The game breaker here is Tycho's mana regeneration power, which doubles the amount of mana you get per turn. Combine this with Moira's stun spell (the mana cost of which increases by one for each use) and you can keep the boss locked down for basically the entire battle simply by having two of your monsters use her as a trainer and alternating between blocking and stunning, since blocking makes the character's next turn come faster. Then let your heavy-hitters go to town.
The vampire mime in Episode 1 has full-party attacks with a very short block window, requiring near-perfect reflexes to manage a solid block. Getting a partial is often the best you'll manage, which means you'll spend half the time suffering from an attack debuff.
The final boss in Episode 1 is easier to block, but attacks a lot more than the mime does and uses area attacks exclusively until the final phase. Once you hit the final phase, then it gets cheap as hell by spamming a single-target attack on Gabe several times in a row, occasionally doing it twice before Gabe can actually hit back.
The Seamstress in Episode 3 has to be beaten within a set number of turns or she'll unleash a magic spell that will be a Total Party Kill unless you debuff her magic repeatedly. She also has a couple flunkies which will boost her (and their own) attack and defense if allowed to live long enough, which means you need to spend time killing them.
Dr Missingno in Episode 4 has a ridiculous amount of health, and like the Seamstress it needs to be chipped away down to nothing within a certain timeframe or he will unleash a Total Party Kill attack.
The Reaper in the same episode has a One-Hit Kill... and nothing else. Every attack kills a member of your party. You better hope you can beat him before his kills catch up to your ability to revive.
Blocking in the first episode, which is easy half the time and unbelievably difficult the other half. Against some robot attacks, blocking is literally the difference between Scratch Damage and a One-Hit KO, and these attacks occur almost instantly. This gets better as your level increases, allowing you to tank a few non-blocked hits, but not by much. The sequel was a lot better about it, both in blocking being easier and having enough health to survive regardless since you start out at a high level to begin with.
That mini-game you have to do in Episode 2 when you're thrown into the asylum. If you don't like puzzles, you're going to have a rough time with that.
Squick: There are several buffs which involve urine, one of which your character takes intravenously.
That One Attack: Any status effect attack in the first two episodes counts, since you can only have one active at any given time, but attack reducers take the cake. Unless you wait it out (which you can't do in the sequel) or rebuff, it takes you out of the fight. The vampire mime in Episode 1 is especially bad about this, since its Wall of Hellfire attack is nigh-unblockable and gives said status effect.
That One Boss: The Usurper from Breath of Death VII shows up as Evil King in Episode 3. Like the original, he fully heals after a few turns, with the added effect of getting a huge stat bonus that lets him attack faster than all your characters and hit extremely hard. On Insane, the fight is basically unwinnable without major Level Grinding beforehand. Thankfully, a patch was released that removed the speed boost.
That One Level: The level in which That One Boss above appears is almost as hard as the boss himself, due to all the enemies having a huge boost in health compared to what you've been facing (on an average of +2000 for any non-fodder enemy), as well as difficult-to-kill mini boss enemies in every dungeon section.
They Changed It, Now It Sucks: The third and fourth installments being done in Zeboyd's retro style as opposed to Hothead's 3D graphics has earned some criticism. But it was either that, or they never come out at all.