I like the Sun Beam (Doc Smith). And even more I like how it reappears in Ringworld. Lucky guess or brilliant prediction?
Requires a Class 666 Federal Firearms License. Launch system not included. 
Whipped it up when I was fleshing out the background for a SF book I’m working on.
Waaaay too much time on my hands.
Since Ice-Nine’s already been mentioned, I’ll list a few of my favorites from Transmetropolitan.
The bowel disruptor. I so want one of these. “Now, what setting? Watery, loose…prolapse.”
The Marr Special-Issue Nervebreaker. Kinetic burst, concussion wall and flamethrower all in one.
And the good old-fashioned low-tech Chair Leg Of Truth.
“Nuke 'em from orbit. It’s the only way to be sure.”
Of course, if you take all the books into account, that wouldn’t work, either.
And I’d thought of the Weapon Shops of Isher… but if we’re speaking of general coolness factor of a weapon, who wants one that can only be used defensively? Man, I want one I can use to carve manhole covers out of steel bulkheads, shoot out the guy wires on the main communications tower, and then flip it upside down, hop on, and RIDE AWAY TO GLORY!
Hm.
Perhaps Larry Niven’s “Slaver Weapon” is what I really want. Depending on what setting it was adjusted to, it fired bullets, neutralized nearby energy fields, fired a total-conversion energy beam, and sprouted footrests so you could skate to safety on the thing…
…of course, it was notoriously picky about who was trying to wield it…
Er, that’s the “Soft Weapon”–a Tuncnip (or turnip or however it’s spelled–I’m on the road with no access to books) spy weapon. It does match your requirements pretty closely. To keep it happy you have to convince it you are not a slaver.
Which is harder than it might appear on first blush: Slavers were telepathic, so you didn’t have to be a Slaver to be aligned to them. What was worse was that the one Soft Weapon found was paranoid, by ‘modern’ standards. (Relics of ancient, genocidal wars tend to be that way, don’t you know?) So, since it never met a species like yours, you’re screwed.
My favorite SF weapon is the ‘warp grenade’ and ‘warp cannon’ from David Weber’s Dahak books. Taking your target and leaving it in hyper space, without a spaceship. Just a faint ‘poof’ and no more target.
As far as coolest-looking sci-fi weapon I would have to go with Han Solo’s blaster pistol.
Here is one version
http://www.swtroopers.com/props/props_hanblaster.jpg
and another
The Tar-Aiym Krang was a pretty nasty one from memory (from the book of the same title). Nothing like a collision with a black hole to dampen your enemy’s day.
Of course that reminds me of the short story “The Hole Man” where a black hole from an ancient communication device was used similarly.
I seem to recall some books with a C+ missile/cannon something where the missiles would accelerate to near C (or slightly over) so their relativistic mass was tremendous on impact.
In the 1973 made-for-TV movie Genesis II (your basic scientist-goes-into-suspended-animation-and-wakes-up-in-the-future plot – see http://www.imdb.com/title/tt0070101/?fr=c2l0ZT1kZnxteD0yMHxzZz0xfGxtPTIwMHx0dD1vbnxwbj0wfHE9Z2VuZXNpc3xodG1sPTF8bm09b24_;fc=17;ft=55;fm=1), the ruling mutant caste (they have two hearts and two navels) of the city of Tyrania control their human slaves with a baton called a “stem,” which, touched to the subject’s skin, can induce intense physical pain – or pleasure, depending on how the wielder sets it. Very versatile, no? Not exactly a “weapon,” of course. It would need more range (like a Puppeteer tasp) to be useful in combat.
emarkp Would that be anything like Acme’s Instant Hole, once used by Wiley Coyote in his nwever ending pusuit of Road Runner?
Blatant ripoff of the Agonizer in the alternate-universe Star Trek where Spock had a beard.
The Improbability Drive. Not a weapon per se, but if it can turn incoming missiles into a bowl of petunias and a sperm whale, imagine what else you could do with it.
Space Ghost’s Power Bands Those two bracelets give him at least twelve types of offensive and defensive capabilities:
And he has one of the coolest battle cries ever!
Another great Space Ghost site
[QUOTE=The Vorlon]
I do have a soft spot for Wunderland’s answer to the Slaver disintergrater…
QUOTE]
The Wunderland Treatymaker! I was just thinking about the disintegrator/digging tool as a weapon being pretty cool, but the Treatymaker was a great idea!
This page:
http://technovelgy.com/ct/Science_List_Detail.asp?BT=Weapon
has a list of pretty cool science fiction weapons and descriptions.
“Activate Interlock! Dynatherms Connected! Infracells Up! Megathrusters are GO!”
Not to forget “FORM BLAZING SWORD!”
A couple superhero weapons:
The Sandman’s gasgun - or, more specifically, the gas itself. Puts the victim into a state of semi-conciousness, where they’re vaguely aware of the world around them (albeit often filtered through a dream-state), and incapable of lying.
Green Lantern’s ring. More a tool than a weapon, its ability to do pretty much anything the weilder wants renders it a really impressive weapon when that’s called for.
And, my final suggestion:
The Composite Superman/Batman robot. Just for the sheer demented creativity for it.
Take the Composite Superman, combine him with Mazinger, and build the whole thing out of metallo (the metal, not the psycho-cyborg also built out of it). Moved that whole story-arc from ‘Pretty darn good’ to ‘freakin’ brilliant’.
Bah, Predaking would pimp-smack Voltron inside of three minutes… Though calling them “weapons” wouldn’t help your life expectancy any. 
I like the Cohe wand from Christopher Hinz’s Liege-Killer and its sequels. It’s a hand-held slice-n-dice energy weapon like a lightsaber, but the beam is flexible like a whip so the wielder can get you even if you’re not in his line of sight.