Some Anvils Need to Be Dropped: Even with the whole "transplanted organs will make a host for an ancient evil" thing in the story, Sena still tries to show that organ transplantation is a beneficial practice.
Squick: Anything Eve does, like creating a body, or raping Toshiaki, or raping Mariko.
Special Effect Failure: The fire is even awfully designed for its day, not appearing anything like fire or flames actually look. Even contemporary music videos were better at depicting CGI fire at the time.
To be precise, the game is written to function as a standalone sequel. Maeda makes a few mentions to a similar incident in Japan happening before, which is referring to the events of the book and movie.
The awesome final boss theme, "U.B.", and also "Escape from U.B.", a creepy song which really provides extra tension during the final escape sequence. Escape from U.B. in particular got a kickass remix in The 3rd Birthday.
Mitochondria Eve-2 is a sadistic collection of sapient mitochondria who formed into a singular, powerful figure. Having materialized in Maya Brea's kidney after being transplanted into actress Melissa Pearce, she later takes over her body by killing competing mitochondria and attaching to her cells. She plans to use Melissa to give birth to the Ultimate Being, a lifeform far more powerful than her with the power to instantly destroy humankind. Taking complete control over Melissa's body during an opera performance, she causes everyone's cells to burn up and combust. Knowing that Aya Brea is after her, she uses her powers to turn animals, both alive and undead, into vicious monsters to kill her. Working with Hans Klamp, she has him create special sperm to help her give birth, later having him gather up a group of people—including Daniel's ex-wife and son (though he ends up escaping)—to Central Park, where she melts them into a slime and has it hide in the sewers to later serve as her uterus. Having made Manhattan a complete ghost town due to her actions causing a widespread evacuation, she later raids the police station, having her mutated animals murder and injure the surviving cops. Obtaining a sample of Klamp's mitochondria-free sperm, she later gives birth to the Ultimate Being, tempting Aya to join her in her cause before trying to kill her after she refuses.
Hans Klamp is an anti-social misanthrope working with Eve-2 on her plan to eradicate humanity and allow mitochondria to take over, seeing them as superior to humans. As a teenage intern at St. Francis Hospital, he transplanted Maya Brea's kidney and cornea into Melissa and Aya before getting fired over selling patient records. Partnering with Eve-2, he removes mitochondria from his own sperm to allow Eve-2 to easily give birth to the Ultimate Being, prideful to be involved in its creation. He later invites people on an HLA list to a play in Central Park, where they are turned into slime by Eve-2 to be used as her uterus, causing the deaths of many, including Daniel's ex-wife Lorraine, with his son, Benjamin, escaping just in time. When Aya discovers his plans, he tries to kill her with a scalpel. Refusing to face arrest, Hans orders Eve-2 to burn him, chastising Aya for wanting to save him. Before his death, Hans engineered Maya's body to unleash another Eve once Eve-2 gives birth to the Ultimate Being, starting the plan all over again should Eve-2 not succeed.
Disappointing Last Level: Day 6 starts with a multi-stage boss, which, while impressive, is no match for the Suspicious Video-Game Generosity that immediately precedes it. Defeating it leads to a chase through the maze-like interior of a ship which, while certainly tense, requires no wrong moves whatsoever through the unmarked tunnels, with the slightest mistake or deviation being punished with a One-Hit KO. And failing to realize one has to activate the boiler along the way just makes the chase Unwinnable. Also, you'll have to re-fight the final boss and sit through unskippable cutscenes and dialogue first each time you try.
Demonic Spiders: Flyman and Bacterium, which have the ability to spew out green acidic puddles which slow Aya down to a crawl and fire a red round projectile which poisons her.
Game-Breaker: The Super Toolkit available in New Game+ (aka "EX Mode"), although the upgrades are still limited by the attribute "donor" items and the upgrade capacity of the target. And whether you collected all of the Rare Trading Cards for it; miss a few and you'll be awarded a lesser version that destroys donor items.
You play your cards right, you can put together a pretty cheesed up weapon on your first playthrough. How about a handgun that fires two salvos of flaming shotgun rounds? Yes please!
In an LP, the player managed to put together a gun that fired grenades full of acid and liquid nitrogen in shotgun spray.
Upgrading a gun's ammo capacity and range to high enough levels can let you attack monsters from any spot on the battlefield (unless they fly/dig off screen) and never having to reload.
Adding the shotgun effect to regular rifles or handguns makes the things effectively fire flechettes for full effect in a cone, neatly breaking the rate of fire problem noted in Awesome, but Impractical.
Guns that have the "Enter 2 (or 3) Commands" effect can offset the rate of fire problem described above, allowing you to shoot multiple times but have the attack power be based on a single bullet per shot instead.
Even moreso, you can and do use a Power as a command, meaning that that mod can have you fire off multiple powers, possibly mixed with gunfire.
Powering up your armor enough can let you be completely immune to damage from almost every enemy attack and you will need it when tackling the higher levels of the Chrysler Building.
You can also modify your armor to make you immune to every single status ailment in the entire game, with the exception of Defense Down.
Paranoia Fuel: You have a mitochondrion in every cell of your body. They're the chemical engines of life, and without them you'd die in minutes. And they're of such alien origin that they even have their own DNA, rather than being coded in the nuclear genome that describes every other aspect of your phenotype. What if one day they decide they hate you, and they should revolt?
Signature Scene: Contenders are the disastrous opera scene in the beginning of the game, Aya confronting the pregnant Eve in the museum, or/and Aya vs. Maya in the Chrysler Building.
The Sheeva boss fight where Sheeva transforms into the monster while the boy and his father watches in horror turning it into the monster it can hit too close to home for anyone who has to put down their dog, his father tries to shoot Sheeva but it was too strong for him so the boy pleads for Aya to kill it! Eventually, Aya does it's very sad because Sheeva was such a nice dog and the boy loved that dog but Sheeva knew she was turning into the monster as she tries to run away from him so she doesn't hurt him. If you're a dog lover, then you'll cry during this boss battle.
Fighting Maya isn't terribly difficult until you start to whittle her HP down. She can perform several kicks that you can't avoid at all and she can also do a charged up flying tackle that is both unavoidable AND doubles as an HP to 1 move. What's even worse is due to the game employing Collision Damage, if you get stuck on top of her after her tackle attack ends, you can take additional damage and possibly die. When Maya has her helpers summoned, attacking her has a second helper appear that heals her for 1000 HP and additional healing raises it by an extra 1000 points (And good luck figuring that one out). You NEED Auto Heal and plenty of Medicine 3 and 4 to be able to survive the fight since your turns will never come up fast enough to let you heal yourself manually.
Unwinnable by Insanity: After defeating the Ultimate Being, it starts to chase after you and gradually picks up speed. When you reach the boiler room, Aya notes that she should overload it so that the ship explodes and kills the creature. However, you can actually skip the self destruct sequence and keep going. If you choose not to blow up the ship, the creature will move so fast that it will catch up and kill you instantly no matter what you do. Only by rigging the ship to explode will the creature move at a pace that keeps you on your toes yet still give you a chance to escape.
The Woobie: From what we learn of her, Melissa Pierce. She was an Ill Girl since her youth and all the way up to adulthood was hooked up on medication. Despite that, she struggled to become an opera singer and had to share her part with someone else. And then on her opening night, she was taken over by Eve thanks to a kidney transplant supplied by Maya back in her youth as well as further medication by Klamp that would make her body even more susceptible to Mitochondria Possession.