I always felt that after Doom's BFG, any attempt at a 'massive ultra-awesome-powerful-weapon' is destined to be a poor immitation. And you can't get more direct than just stating the initials for 'Big F------g Gun'.
But that aside, in shooters I felt the first Fear had the right balance of realism and innovation. The sequel tried to go more 'out there', but the weapons lost their weight/feel, and removing the 'lean' function changed the playstyle drastically. So I'd say as a 2nd choice, several of the weapons from Fear - the last gun you get in the game, with its 4-explosive-rocket rapidfire was interesting, as it was incredibly powerful but still needed to be used tactically and with situational awareness, as the game's relatively grounded approach to gunplay meant that you had a good chance of blowing yourself up if using such a powerful weapon in an run-n-gun fight. It had some neat twists on the standard weaponry as well that made you think past the straight up: dual-pistol for ammo conservation, shotgun for close-range, sniper for distance, assault for everything else. Instead, the sniper rifle was also a 3-shot autofire enabling a degree of ranged run-n-gun, but with severe ammo shortages. The shotgun was powerful, but the AI was excellent at taking out campers (they'd usually do 1 assault rifle providing suppressing fire, another 1 throwing in grenades to flush you out, and 2 shotguns moving in to pwn you as you're forced out of cover), so you had to use it on the run. You had a laser that doubled as an excellent alternative sniping rifle and an ultra-powerful weapon against armoured opponents, again with ammo troubles. Or you could use a needler, that was marginally less effective than the assault against normal troops, but excellent against armoured troops and could substitute as a makeshift sniping option. And you could only carry 3 - which meant that you were always stuck having to sacrifice some area to cover others, meaning that a powerful but situational weapon like a dedicated sniping weapon or missile launcher isn't necessarily a better choice than a less powerful but more adaptable weapon.
For melee weaponry, I'd go Dakkon's Zerth blade from Planescape: Torment. Too long to explain here, but anyone who has played the game will understand immediately.
Edit: and how could I forget the nanotech blade from Deus Ex. A much simpler design than what we often see today, but I actually liked that. It's good to see a sword that actually looks like it's intended to be used, rather than something so absurdly decorated that it's implausible for any use other than hanging on a wall (i.e. your standard computer game blade).
