I kinda like the neutron bomb from the Kurt Vonnegut book. Which book, you ask? I’m buggered if I can remember.
The BFG-9000 was always a blast, too.
“Deadeye Dick”, but that’s not a fictional weapon.
Ahhh, yes, the ROD. The only problem is, you have various high level fighter lackeys walking up to you and saying “Give me the ROD!” That would scare the peasants girls off, right there.
Like ninjas and hot-fudge sundaes, sword-chucks are incredibly sweet.
That is all.
Tenebras
Skadwe, a splinter of death’s door used as a sword, if it is to be my own personal weapon.
As for my favorite fictional weapon, it would be the “Very stupid weapon, do not use.” one from that Peter David star trek book.
The Black Sheepinator, from Ratchet & Clank 2. It’s a ray gun that turns enemies into black sheep, that are irresistable to other enemies and explode on contact.
The chicken gun from Muppet Monster Adventure was pretty cool too.
I’d second NoClueBoy’s nomination of the Tasp, but I don’t think I’d use it as a weapon. No way am I going to waste its batteries on someone else.
As for actual cool-looking destructive weapons, I like the mobile fortresses from the new Appleseed movie. Very cool.
And Kaneda’s laser rifle from Akira was pretty nifty.
Okay, that’s five; I’m over my limit. (But I haven’t even gotten to edged weapons…oh, well)
My first choice was the time-travel belt as used in David Gerrold’s The Man Who Folded Himself, but that’s not really a weapon.
So I choose Space Ghost’s Power Bands, or whatever he called his gauntlets. If his flight and invisibility are provided by his costume, then I choose Space Ghost’s complete costume, Power Bands included.
I like the pistols they used in Underworld – autofire mode and infinite bullets. That’s got to come in handy.
The two weapons the bird people used in Mom and Dad Save The World.
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The light grenade. You pull the pin and then set it down. Someone picks it up and they disappear, but the grenade stays. To make sure they pick it up, it says "Pick Me Up’ on the side.
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A rock. You pick up rock and then hit people with it.
Dare I mention the dreaded and hilarious Morph Ovum?
We should break this into two catagories, personal weapons, and weapons of mass destruction.
I like the Phaser as a personal weapon, although it is also a weapon of mass destruction.
Give me a Foton Torpedo when I want to destroy another ship, or do some serious damage to the inhabitants of a planet.
“Photon”–PHOTO*N–photon.
Two nominations - the gun from The Fifth Element and the inertialess planets from the Lensman series of EE Doc Smith.
C’mon – nobody wants Excalibur? (Of course, there’s some confusion as to whether that’s the sword in the anvil, or the sword proffered by the Lady of the Lake. Or both. And the scabbard is actually more remarkable.)
Give me a phased plasma rifle in the 40 watt range.
Hey pal, just what you see. 
The nanobombs in Spider Robinson’s Starseed have perhaps the most fiendishly lethal mode of delivery in fiction.
Niven’s Ringworld meteor defense is perhaps the most awesome weapon.
You mean 40 Mega Watts, right? I got light bulbs in my refrigerator that do 40 W. 
I’ll be happy if I could get my hands on the Gravity Gun from Half Life 2.