driftrider

If you're talking about PRODUCTION handguns, I think the nod goes to the T/C Encore pistol. T/C makes pistol barrels chambered in rifle cartridges up to .375 H&H I believe. Magnum Research also makes their BFR in .45-70, which with 500gr hardcast bullets would be a real handful.

And if those don't beat you up bad enough, I'm sure there are a half dozen custom barrel makers/gunsmiths that'd ream an Encore barrel to whatever cartridge you feel masochistic enough to try. Or you could get a Class III permit from the BATFE and saw off a SxS 10 gauge to about 8" and then drop both hammers on two 3" 2-1/4oz. loads. That'll more than get your attention. Or maybe a .50BMG in a 10" or so barrel without a brake...just make sure your insurance (health and life) are paid up, 'cause you'll need one or the other when you're done.

I personally am quite fond of the .454 Casull, and will be hunting with mine come fall. With 250gr bullets and sub-Max loads it's not unbearable to put 50 rounds through it in an afternoon (did it today with mine). The .454 Casull is, realistically, all the handgun one should ever really need. If the critters you're hunting are big and mean enough to need more power than a full-tilt 300gr .454 Casull can provide, then IMO you should leave the pistol at home and hunt with a rifle.

I've shot the .500S&W and while I'm impressed with its power while still retaining decent shootability, I believe that most non-handloaders can't afford to shoot the thing enough to master it, and there is no option for a lower powered alternative cartridge for economy practice/plinking for the .500S&W (like the .45 Colt is for the .454 Casull). Reduced power loads are also problematic because of the extremely large case capacity resulting in very low load density and possible pressure excursions.

Mike