Demonic Spiders/Four X

These will happily rain terror on your Player Mooks for days on end.

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• Barbarians in Civilization. They aren't much trouble early on, when they're animals (which won't enter your cultural borders) or Warriors (which are only dangerous to Settlers or Scouts). Then they discover bronzeworking. Barbarian Axemen will wreck your infrastructure like nobody's business, are a pain to take down in melee, and tend to come in packs - and they usually bring at least one Archer with them just to keep you guessing. The really irritating part is that, after about 800 BC on any difficulty harder than Settler on the expansion packs, these guys never stop coming. Build the Great Wall as soon as you have access to it, or, barring that, keep Archers near your important tiles.
• Xenon "M" interceptors in X3: Terran Conflict. While they're poorly shielded, they come in huge swarms, and 90% of them will mount Pulsed Beam Emitters -- rapid-fire, lethally accurate lasers that do incredible damage to shields. A single M can strip down the shields of an M3 fighter very quickly on its own -- add in several dozen friends and you basically need a capital ship to kill them all without dying instantly in a hailstorm of (nearly) Hit Scan weapons.
• The Dread Lords in Galactic Civilizations. Any conflict involving them is going to be bloody, to the point where their constructors can go through mid-level ships like knives through butter. Also, ten Dread Lords infantry can conquer a planet. We recommend either swarm tactics of a sting-before-you-die suicide attack nature, or blowing up their sun.