Cross genre polination.
I.e: the party keeps getting harassed by someone with abilities that appear to be magical in nature but the person doesnt set off any magic detectors. Ultimately they discover that the guy is actually a cyberneticist from an alternate world. Watch them suck down some high technology for a change. Or better yet make the guy a mage from the WoD
Or my favorite: the Attack of the Gazebo!
This is a story that was repeated to me by a good roleplaying friend.
DM: You step through the tree line and are confronted by a large white gazebo. !0 feet high and five feet wide at the base.
Playa1: Hmmmmmmm. Does it look impressed by our vast array of weapons?
DM: No. It’s a gazebo.
Playa1: Eeek this thing sounds pretty tough.
Playa2: Still we dont know that it’s hostile maybe we should attempt to communicate with it?
DM: ummmm… guys…
Playa1: No! Thats exactly what he (points at DM) wants us to think!
Playa3: I’m with you! I say we fuck it up!
Playa1: Right lets go! Playa2 you cast dimensional anchor so it cant teleport away. Playa3 you cast ‘blind’ so it cant fight back. I rush up and smack it with my +3 life draining sword. (rolls dice) YES! a critical hit! This bitch is going down!
DM: (uncomfortable pause)
Playa1: do I get any life from it?
Dm: No. It’s a gazebo.
Playa1: Damn! Must be undead or elemental. Well I’ll hit it again! (rolls dice, scores big numbers) Well? Did my strikes seem to hurt it at all?
DM: NO! It’s a gazebo.
Playa1: What?! Sweet Jesus and Mary! What have you unleashed upon us this time you bastard?
Playa2: fuck this! I’m retreating to a safe distance. If we ensnare it then it wont be able to follow.
Playa3: Done.
Playa1: Alright fine I break off and retreat.
The players then spent the better part of a day hurling fire and molten rock and poisoned arrows and acid down on the poor defensless gazebo. All the time recasting ensnare (or something like it) to keep the hellish creature at bay.
One final idea: HIV.
Have a defeated enemy make a suicidal attack in order to stab one of the party with a completely innocuous weapon. It is only later when they start getting flu-like symptoms and spots that they realise they are developing full-blown AIDS.
Nasty.