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.
Those cherubs. THE CHERUBS! Even in Casual Mode there's a good chance you'll get killed in that fight.
The black slime golems are worthy runners-up, considering you fight two of them in cramped locales while being blasted by venom crawlers.
Toss all possessor ghosts into the pile: not only do you have to remove them from their human hosts before actually busting them, but they can also turn the other Ghostbusters against you as easily as they do any other human. Expect a lot of running and sliming to keep yourself alive.
There's the Grave Golems that make the Black Slime Golems look like patsies.
Evil Is Sexy: The Spider Witch in the Realistic versions of the game. You wouldn't have guessed from her slashed mouth with fangs, unless you're into that, but in life she was a bizarre yet attractive woman. This was her main way of attracting her victims.
Fetish Fuel: In-story example: If you listen to the messages after the museum level, you'll hear a call from a guy asking the Ghostbusters if they'll hook him up with one of the Possessor ghosts you fought.
Goddamned Bats: Has this in the form of flying books that screech like bats. The spider chandeliers qualify too, but they're not nearly as annoying as the Book Bats who come in much greater numbers. The presence and, in later levels, commonness of "little destroyable ghosts" is a commonly-stated strike against the game.
The Stone Cherubs. DEAR GOD, the Stone Cherubs.
Harsher in Hindsight: While dealing with a new haunting at the Sedgwick Hotel, Egon has a line saying "people die every day." Five years later Harold Ramis would tragically be one of those people.
The fact that this is the last time we will see all members of the original Ghostbusters.
Nightmare Fuel: A section of the library full of the ghosts of children. Even Ray is unnerved as you make your way around the room.
Also, after one fight with a heap of Book Bats and a few Paper Constructs, after the fight is over, you hear a disembodied voice scream out "NO! NOT MY BOOKS!"
Nightmare Retardant: The Juvenile Giant Sloar, when looked at from a certain point of view, is Gypsy on steroids (and possibly roaring drunk, too, what with all the puking it does). Shandor's Destructor form can be seen as this, too: all the potential possibilities, and he limits himself to a stereotype cartoon devil.
Possibly as a result of how stereotypical the devil form is, the "creepy robed man" of the stylized version comes off as legitimately more menacing.
Stop Helping Me!: In the 2009 game the other Ghostbusters do try to carry their weight, but expect to be reviving them every minute or so. You shouldn't complain too much, though, since they'll be doing the same for you quite often.
That One Achievement: "Nice Shootin', Tex!" Complete the game with less than $100,000 in property damage. How hard could that be? For reference, it's easy to exceed a million dollars in damage in the Times Square level alone.
That One Boss: Azetlor. He can move fast, has attacks that can drop you, Egon, and Ray in very few hits, has some of the highest health in the game, a fairly small vulnerable area, and can summon Book Bats to help him. Many Rage Quit at this point. You need to move fast and continue reviving your teammates if you intend to survive The Collector.
Uncanny Valley: The realistic version of the game on the PS3 and 360 renders most of the characters fairly close to the way the actors looked in the movies. While it is still somewhat stylized, there are more than a few moments that look almost life-like.
In some of the cutscenes using the game's graphics as opposed to CG, the Ghostbusters tend to move more like marionettes than people, and it's a bit unnerving. Even when the animation is good, people tend to find Ray to be the most unsettling due to the fact that the developers paid so much attention to making the characters look like their actors circa 1991 that they not only included Dan Aykroyd's Mismatched Eyes, but got the right colors on the right sides of his face (left eye brown, right eye green). Realistic faces + jerky animation + often-questionable lipsyncing = unsettling character models.
Vigo the Carpathian, the Big Bad of Ghostbusters II, is reduced to nothing more than his painting in the game, unable to do much of anything except talk. To add insult to injury, the painting is owned by the guys who beat him—the Ghostbusters.
The game also made Stay Puft much weaker than before, to the point the player character can take him on. It's actually stated in the game that Gozer's second manifestation as Stay Puft was much weaker than the first.