Nobody knows this one, but I loved the D-Gun in Total Annihilation. Basically, it was this short ranged gun that could be used to destroy any enemy in one blast (and could destroy several if aimed well), making early game rushes impractical, and keeping the Commander relevant as a combat unit all the way to the end. It made you fear the Commander in a rush, no matter how big your army was.

Vergils Yamoto,Dantes Alastor.
Clounds Buster sword,Sephiroths Masamune.

Chicago Typewriter from Resident Evil 4. The deadliest weapon ever made. Of course it makes the game almost pointless playing with it as it takes a second to kill any boss no matter how tough he might think he is. As for zombies they haven't got a prayer.

I've been thinking this for sometime now.  What is the story behind Sephy's long sword?  Why is it so long? Powerful??? Etc..

Singularity Cannon from Unreal II. That stuff puts everything else to shame. IT SHOOTS BLACK HOLES! You just don't mess with that stuff.

Sephiroth's long ass sword.

Edit: beaten.

the lancer! man what isnt cool about a chainsaw on a gun

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Samus's Arm Cannon/Power Suit. It can be upgraded, fire tons of missiles, unlimited beam ammo(except light and dark beams), and it has the Morph Ball.

Then again the suit has many weapons... So if I had to pick one I'd have to say the Hyper Beam from Super Metroid.

The hammer of Thor.
I also like the Red Ryder carbine-action 200-shot range model BB gun.