Do I only have to pick one??
Then it's probably Painkiller's unsung hero, the rocket launcher/chaingun. This weapon is, in most situations, considerably more effective than the infamously epic electrodriver. Its rockets have a good fire rate and just one of them can happily reduce a cluster of enemies to Unreal Tournament-style bodily chunks. The chaingun bit is the most accurate long-range weapon in the game, at least until the expansion, and deals out shedloads of damage.
Or possibly the AP SMG/flamethrower from the expansion. The SMG does more damage than the chaingun, even after its lower fire rate is factored in, and can rip through anything - hard enemies, tanks, you name it - with alacrity. The flamethrower is just gold. The effect is stunning, and sweeping it across a group of enemies ignites both them and the ground around them, creating a burning, dying mess that can ignite other baddies wandering into the vicinity. (And you, if you're not careful.)
Actually, no, sod it. It's Unreal Tournament's Enhanced Shock Rifle. Instagib, people! A gun that, every time it fires, hits its target instantly and - if said target is human - bodily disassembles them in a shower of blood. Not only that, but everyone has it. It makes the games faster-paced, more fun and more balanced. Win.
(Runner-up goes to UT3's Stinger minigun. It's three tri-barrelled rotary miniguns held in a rotary mount.)