That One Boss / LISA

• Joy mutants are devastatingly powerful and half of them come with at least one perma-kill attack. Thankfully, a majority of them are optional on Normal mode... except for Charmy, who is fought in Area 1. Despite being unable to use its one-hit kill move, Charmy can easily one-shot pretty much anyone in your party that isn't Brad, and has a mountain of HP, especially this early in the game. The extremely limited roster of party members doesn't make this fight any easier, and while it is possible to grind on the snakes and shadowy figures in this area, doing so quickly becomes inefficient. While it might seem smart to just unload on Charmy with firebombs, doing so makes the Men's Hair Club much tougher to handle.
• If you enter Factory Town, when you come out, you'll be ambushed by the Road Scholars, who will demand all your mags. If you choose not to give them up, then you get sucked into a fight with a five-man gang. They all have very respectable HP and can hit ridiculously hard for this stage of the game, and worse yet, several of them can Stun or Paralyze your party members. Often, this ends with the five of them whaling on your helpless, immobilized party. About the only way to win this fight is to know it's coming and either bring Firebombs, grind Brad up enough to use Head Slide, or just fork the mags over. Losing this battle will result in the town getting blown up, along with the powerful party member Mad Dog. Oh, and don't try to be smart and spend all of your mags beforehand; the Road Scholars will just blow up the town without a fight.
• In Normal Mode, Sweet Tea Rakeem is a forgettable early game boss. In Pain Mode, however, he gets a friend - Vic Cherry. While they don't hit as hard as mutants do, they hit much more consistently, and they have sky-high agility, meaning they will always go first in battle. They also resist most status ailments, being immune to Fallen and resistant to Stun, Scared, Sleep, and Paralysis. It's the first real challenge Pain Mode offers, and a pretty major stumbling block if you aren't ready.
• The two required Joy Mutants that are only fought on Pain Mode, Herb and the now-mutated Hawk, are especially frustrating due to the fact that, barring the basic Joy Mutant bite attack that they use more, overprioritize their perma-kill moves, meaning that it is very likely to see your party members be quickly picked off until they begin to wail on Brad. That, and they are not only immune to Fallen, but Paralysis and Scared as well, meaning you will NOT be able to catch a break with either of them.
• Peter. He has pretty solid HP and is tied with Wally for having the second highest Attack stat (and the highest of any required boss), meaning that he can easily KO a party member with ease. But that's not all; he comes with not one, but two perma-kill moves, and he loves using both of them, so have fun trying to keep all of your party members' heads on. Peter's only saving grace is that his Agility is practically nonexistent, but he's still a very powerful killer.
• Wally. Wally has three forms, each of which packs 4-digit HP (which, when added together, gives him 19,000 HP; the highest of any required boss and the third highest overall) and fairly respectable defense with Fallen immunity on the side. Wally can also Laugh, which, while possible to miss, is more often than not capable of inflicting the entire party with Scared (causing the victim(s) to waste their next turn) and the seldom-seen Depressed (a ridiculously-crippling debuff that harms your Attack, Defense AND Speed) at once. If you've run out of items and SP during the first two forms, then you're in for a beating.
• Every area has a gang of multiple men that can occasionally kidnap a party member, with the option to either pay their ransom or attack them, killing your party member in the process. Even if you attack the Blue Rockets or the Pretty Boys, they aren’t that terrible. Then there is the Gale Motorcycle Club, where the choice to fight or pay up is made for you. You get to deal with Rex Thunderstorm, who is one of the most aggressive mutants in the game, and about as tanky as Peter. Not only does he pack Neck Break and uses it with reckless abandon, but he loves using his bike to beat you and your party members into a pulp, which not only deals a fuck-ton of damage, but stuns. Thankfully, he’s an Optional Boss, and nets you one of the best helmets in the game.