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Stealth + archery in Skyrim.  I'll never forget the first time I One-Shot a dragon.  I mean, think about that.

Vanish in WoW.  Want to induce rage?  Vanish right when your opponent thinks they've won then stun-lock them to death.

Not a perk but the .50 Anti-material rifle in New Vegas.  When you finally get one, it's pretty much over.  Same with the Buzzsaw in Far Cry

Blink in Dishonored.

Orlandu's Lightning Stab in Final Fantasy Tactics.  I usually delete him.

A fully powered Calculator in Final Fantasy Tactics can own the entire map.