Either the ants or the Tommy dolls in Zombies Ate My Neighbors. The ants move parallel to you unless you're facing them (in which case they just charge), so it's impossible to get around them without using up a ton of ammo, and they walk off with items lying around (and then despawn when they move offscreen, because that's how games were back then). Oh, and they're the size of an SUV. The dolls are tough, fast, small targets, and don't know when the fuck to die.
More recent game-wise, I'd probably just say gravity.
More recent game-wise, I'd probably just say gravity.