The only things Demonic Spiders help to simulate are controller-tossing rage and loss of the will to go on living.
Jet Pack for the PC has enemies that always fly towards you, are invulnerable, and can fly through walls. Apparently, the recommended way to keep from getting nastily killed by them is to turn off the game.
In Mobile Suit Gundam: Zeonic Front, you play as the Zeon during the One Year War, meaning that in the first part, your only enemies are relatively-easy tanks and missile trucks, and annoying-but-not-too-bad fighter helicopters. The problem arises around mission 6, where you have to fight Federation ace Amuro Ray. Given that his Gundam (as well as his two friends the Guncannon and Guntank) are invulnerable and have one-hit kill attacks, maybe "fight" is a bad choice of words. The objective of the mission is to get within firing range of each suit individually in order to collect data on them; if said suit doesn't blow you away at the near-point-blank range you'll need to collect data, its other two buddies probably will. To wrap up the mission, you have to collect data on their spaceship White Base as well, meaning that you have to stand right next to it with your back to three hostile enemies who can kill you in one shot, even with armor upgrades because mobile suit armor is weaker in the back. To top it off, there is a simulator mission where you have to actually kill the Gundam, which, although no longer invulnerable, is more or less immune to bullets, meaning you have to walk up to it, get behind it somehow, and hit it in the back with your heat axe, and stealth is impossible due to the fact that the Gundam has three sensors (sonar, radar, and thermal imaging) in addition to line-of-sight vision
In the Freespace series, the Dragon-class fighters. Incredibly small profile, maneuverable, faster than you, with heavy shields and powerful weapons. Their armor is weak, but that doesn't help much when every other ship in the game is the opposite, and loading weapons that rip through shields only turns THEM into Demonic Spiders.
Lilith-class cruisers. Not especially dangerous to fighters, but they pack a destroyer-strength beam cannon as their main armament, far in excess of the firepower other cruisers carry. This means that Liliths can warp in and gut friendly destroyers with relative ease, and even one-shot friendly cruisers. Worse, in the original game, they look identical to the much-weaker Cain-class cruiser. The FS_Open version is instead colored pitch black rather than the grey armor of the Cain.
The Terran Aeolus cruisers go the other way and are packed with lots of small guns specifically made to shot down fighters and bombers. Engaging them should only be done in very fast strafing runs and only in large numbers, preferedly with a couple of frigates and destroyers providing support fire. Trying to get inside the range of their flak guns with only a single wings of fighters pretty much means instant death.
In The Babylon Project, a Babylon 5 freeware game built using the FreeSpace 2 engine, any Minbari, Vorlon, or Shadow fighter if you're flying a Starfury, since all three species have way better tech than Earth Alliance. Frankly the Vorlon fighter qualifies no matter what you're flying.
Any third generation VT in Steel Battalion counts. As they no longer appear on radar. Unless you see them in your incredibly narrow field of vision, the only warning you get is the incoming-fire readout. This would be bad enough if they didn't also travel in packs, which is worse if they're with second gen or lower enemies, as you'll probably not realize they're lurking while you deal with smaller fry. The Regal Dress type are particularly nasty, as they like to fire multi barrage incendiary artillery that has a far reaching AOE.
SAM sites, MANPADS', and AAA for any combat flight sim, really.
Any enemy apart from the zombies really. Skeletons have a bow and arrows and can ride spiders, said spiders can crawl through 1-block-high(though not wide) gaps and climb walls, ghasts shoot fireballs at THE CAMERA, and if you attack a zombie pigman, all nearby ones gang up on you!
To clarify, these enemies are programmed to be frustrating. The creeper approaches without a whisper and need only get close to destroy everything, the skeleton zig-zags away from you while firing, and the spider tries to jump on your head (often camping out right atop your roof or wall). The worst place you could possibly face them? A dark, mostly-flat plane that extends infinitely outward in all directions.
There are a few counter-strategies for most enemies (circle-strafing for skeletons, spamming melee attacks for zombie pigmen, zombies and spiders, and dancing at the edge of the creeper's range), but more than one enemy and all bets are off. It doesn't help that they usually spawn around 5 at a time.
Running isn't an option, either, at least against spiders and Endermen. Spiders are faster than you, and can jump farther than you and climb walls, and the Endermen can teleport.
Additionally, the rare and fairly localized Cave Spider lacks the biggest weakness of normal spiders, their large size, and are poisonous. Furthermore, their turf is filled with webbing that will slow you down.
The Grox from Spore inhabit 2,400 planets and will attack in hordes as you go to the galatic core, and if you go to a planet to refill health the Grox's spaceships will all fire their destructive lazers. If you join them (which is very hard) every single other race will go to war with you!
SimCity 4 has them, believe it or not, in trailer trucks. The Rush Hour expansion allows you to undertake driving missions in vehicles such as police cars, school busses, and fire trucks. Bumping into a cement truck is instant death to a police car, but turning on your siren makes them move out of the way (most of the time). Unfortunately, when trailer trucks run away, they leave behind their trailer for you to run into, which will ALSO destroy your car if you run into it.
In Plantasia, weeds and pests start out as minor annoyances in early gardens, but in later levels they're absolute monsters. A swarm of pests can devour all the flowers in your garden in less than 20 seconds if you can't get rid of them. Even a weak little caterpillar can quickly destroy the sun drop that cost you 2,000 mana to buy while you've been distracted killing that leaf-eating beetle that was chewing on your morning glory. The weeds are no better: your plants already need to be watered periodically or they'll die, but let weeds overrun your little field and pretty soon every plant in the garden will be crying out for water. That's bad enough, but if a weed is left unchecked for too long, it starts to spawn more weeds! You can buy multiple weeding tools, extermination tools, watering cans, and really expensive magic spells to help with the problem, but each successive one costs a bigger chunk of mana (the game's currency).
Normally, stray pests and weeds only appear one at a time, but in some levels, a dark translucent cloud will form over the screen, accompanied by the sound of thunder, signaling a massive swarm. If you don't have enough extermination tools or weeding tools at hand, make no mistake, you are screwed.
It gets better! Some gardens start off already overflowing with weeds, pests, or both. One garden has so many weeds that it's impossible to save all the plants that are already growing there; you have to choose which ones to keep alive.
More recent versions of Dwarf Fortress have even outdone the fish. Giant sponges, for instance, have no vital areas and are too large for a dwarven atom-smasher, making them functionally unkillable save by air-drowning, and their "push" attack (the default attack for creatures that can't attack) deals damage based on their mass— read that "giant" part again. Even more "fun"? Undead giant sponges don't air-drown, since they don't need to breathe at all.
The necromancy update has given rise to ambulatory disembodied organs... which have no vital areas and don't need to breathe, so massive damage is the only way to destroy them. These often are the first sign of a necromancer besieging your fortress.
MechWarrior 4: Black Knight, the expansion to MechWarrior 4: Vengeance, brings a lot of Mad Cat Mark II's in use by the player's enemy in that game, which pack quite a punch, can use jump jets, and are hard as hell to kill. You'll see more of these Clan 'Mechs in use by your Inner Sphere enemies in the last op alone than you'll ever see in Clan use in 4: Mercenaries, which is a standalone expansion to Vengeance.
The Clans in the source material use very few Mad Cat Mark II's as the design was created by Clan Diamond Shark specifically for export to Inner Sphere customers. The other Clans, noticing that it wasn't an OmniMech like the original Timber Wolf/Mad Cat and remembering how Clan Diamond Shark betrayed them to do business with "freebirth" Inner Sphere factions, stayed away.
The Nebulon-B Escort Frigate in the original X-Wing. They have a lot of guns for their size, so unlike the much larger Star Destroyers they maintain excellent fire coverage over the whole ship regardless of how close you get, while giving you no gaps in their defenses to work from. Their armament is also nicely tailored to throwing up a wall of lasery hell, so it's not a matter of if you get hit, it's how much. Missions where you're ordered to actually attack one of these things can quickly become a nightmare. It makes it really satisfying to watch one blow up.
Then X-Wing Allianceups the ante with the Lancer-class frigate, essentially a mobile flak battery designed specifically to defend other capital ships from starfighter attack. If you've ever seen footage of American carrier groups under air attack during WWII, that's pretty much what it looks like to come under the guns of a Lancer.
Hardwar has the pirates. Normally they pretty much qualify as Goddamned Bats, as they're lightly armed and fairly easy to dispatch, but a few - and it is important to note that you don't get to know beforehand who those few are - carry Groundbase or Fireburst missiles. The first type will suck you into the ground dealing a good amount of damage and making you a sitting duck for a good few seconds, the second does massive damage to your shields and will kill your engines, which will make you a sitting duck for rather a lot longer than that. A surprise encounter with one of these pirates will usually result in lots of cursing and tons of chaff and flare being expended, and very likely at least some damage suffered. The best way to deal with them is to lure them in the tunnels, where their AI routines become far more limited and this exploitable weakness of theirs can be utilized to your advantage at maximum effect.
The Zombie Apocalypse simulator Infectonator has the Secret Agents in World Dominator. These have a lot of health, shoot very quickly, deal lots of damage to zombies, and worst of all, cannot be infected by your virus clicknote Your main way of converting humans into zombies!
The sequel Infectonator 2 also contains Secret Agents, and introduces Hazmat Guys, basically Secret Agents but with more health and even greater firepower. If your zombies don't have enough attack/speed/defence, expect them to get mowed down by these yellow-suited horrors.
The humans in Wolf. They're the only enemy that carries guns, which are loaded with Instant Death Bullets (if it's not a One-Hit Kill, it's definitely a Two-Hit Kill). They pilot planes and helicopters, which are always One Hit Kills and which are quite fast (fast enough that pausing to bark an alarm to your pack is probably the fastest way to get yourself shot). Ground-walking humans come in two flavors: armed hunters and unarmed hikers; it's impossible to tell which is which until you're shot. The game encourages you to behave as if Humans Are Cthulhu and to give them a wide berth, but even with the number of humans turned down low, they're still quite numerous.
The sixth to final levels of Theme Hospital have epidemics where contagious diseases spread throughout your patients while they wait for treatment. They usually occur when there are too many sick people waiting in the same area, which will happen often, depending on how popular your hospital is. To beat them, you either kick all of them out or cure them within an allotted time limit. Thanks to how hectic the game can be, it's usually easier to just take the fine and you'll be taking a lot of them.
Earthquakes are also difficult to deal with from when they're first introduced; really bad earthquakes can destroy a couple of machines even when they're at full health. And once they're destroyed, the room stays there forever with no way to delete them, taking up what little space you have.
Vector Thrust boasts the DDG-56 and Karel Doorman class destroyers and frigates. Alone, they're not much of a threat, but in a fleet, their combined missile barrages anihilate anything too slow to get out of the way, and if you try to get in close, their combined CIWS fire shreds everything caught in the crossfire. The best way to deal with them is to fly balls-to-the-wall at extremely low altitude at long range so their missiles won't hit you, while spamming long-range anti-ship munitions at them and hope that you don't run out of ammunition.