I’ve shot a lot of different cartridges in various guns. The most powerful cartridge was a .454 Casull - as I recall, from a short-barreled revolver. Holy cowabunga! I thought it broke all the capillaries in my hand. And, I was foolish enough to touch off a second round. I passed on an offer to shoot a S&W 500.
My upper limit is a .41 Magnum.
I will shoot any handgun round, from an appropriately sized handgun. As far as what I would buy, and be useful to me, 460 Magnum or 480 Ruger is probably where I draw the line. The 480 will kill anything that walks the Earth, and won’t break your arm. The 460, will too, and is a great long distance handgun round.
The most powerful I have ever shot is a .357 with some higher power loads though I usually shoot middle of the road rounds with it. Haven’t spent any time in brown bear country in Alaska so haven’t felt the need for anything bigger. Even if I do eventually go there I would likely prefer to have a rifle along with maybe a 10mm semi auto for backup. I don’t have any interest in playing with the hand canons.
I’ll shoot about anything, up to and including a .50, but I won’t purchase anything over a .45, and that needs to have at lease a 4" barrel.
I shot a .44 Mag out of a revolver, and felt enough discomfort in the wrist to tell this is probably the limit of power for me. I know there are Desert Eagles chambered in 44 Mag, would be interesting to compare felt recoil.
44 MAGNUM… it’ll blow your head CLEAN off. So you gotta ask yourself…
I have shot the .44 Mag a lot! I came to a small canyon and went to shoot it at water jugs and even with ear protection the narrow canyon amplified the gun shot and my ears rang for about an hour. I Love the ability to hit a target even if it is behind a block wall or a tree.
.500 S&W Magnum
5 rounds for testing purposes… will never do this again…
I have shot a .454 Casull, .50GI (actually pretty soft shooting). As stated above, as long as the gun is not stupid small for the caliber, I don’t mind shooting them. The largest caliber handgun I own is a .45ACP and .45LC. If I need more power than that, I have long guns. 
I’ve shot .44 magnum a few times and .454 Casul once. Not sure what I hit, but guessing a crow 3 towns away.
By contrast, guy handed me a revolver, and thinking it was .44 mag, I was ready to 1)cry and 2)evade angry crows.
Pulled the trigger, and it was sweet. Shot 5 more and loved it. Turns out it was .41 mag, sweet pearl handled 6" revolver. Guy who originally owned it passed away, left it to the guy who shared it with me, helping to fulfill his deceased buddies desire to have as many people as possible shoot that gun. Cripe, getting chills here remembering that.
Just read on that .50gi, thinking of converting a gun of mine. They say the recoil is relatively soft due to not being a magnum round. Think the fps was like .45acp, +/-…there was another section that mentioned taking down wildebeest with it iirc. So much winning!
@mattm I almost got one, but ammo is kinda scarce on a good day, nevermind these days… It is a very fun round to shoot, especially suppressed. Gun on the left is the first .50GI made by Guncrafter. The one on the right is some type of competition muzzle break. Always a good time when you stop by Guncrafter Industries. 
The more I price the boutique rounds, the more sense it makes to get a .50bmg…well, that’s the line I’ll be using on the wife anyways…
I used to hate shooting 357 magnum and 44 magnum. Then I found that my technique (and possibly the actual grip design) was adding to my discomfort. I now find it fun without discomfort for both of my magnums… at least for 100 rounds or so (more of a financial limitation). For my current area, I don’t see any purpose for anything above a 44 magnum. However, if I were to find a need, I would start testing handguns of the appropriate caliber to see what I could shoot effectively. However, I would think that at that point, a rifle or shotgun would probably be a better choice.
That being said, I think it would be kind of cool to have a 12-14" trapper-style lever action rifle that accepted the 460 S&W Magnum, 454 Casull, and 45 LC. However I think these short lever action rifles with full shoulder stocks were banned long ago as SBR’s…
Mid-range .44 Magnum is as powerful as I go, Full house .44 Magnums have long ceased to be any fun for this old man.
The Red Hawk is tops for me.
I only shoot it every six months so there is a reason to clean it before lubing and staging it in my humble hacienda!
I got to fire a friends S&W .500 w/7.5in. barrel. What a beast. Fired 12 rounds, if you have fired large caliber revolvers before and know what to expect it is controllable even double action.
Expensive to feed tho. I could have bought his for $1000.00 but other then bragging rights I didn’t see the point, no Buffs or Grizz around here. I don’t see the point of shooting large calibers in short barrel’s just like I don’t see the point of rifle barrel’s less then 16 inch’s. 
For a while I owned a .500 S&W with a 4” barrel and shot it pretty regularly. It was very manageable. Sheriff Jim Wilson used to double tap his all the time. That was not bad in comparison to my ultra light .44 mag S&W 329 which I also shot regularly and was also very manageable.
The absolute worst was when I decided to shoot some 300 gr reloads I put together out of my old 4.5” Ruger Blackhawk. THOSE were T-Rex killers. Still have some and they still put a smile on my face.
It’s all about form when shooting the big boomers.
…Do you feel lucky today? 
Compliments of Harry Callahan.
The most powerful that I have fired is Harry’s S&W Model 29 .44 mag. (They were very popular back in the 70s after the movie came out.) Probably the most powerful that I fire on a regular basis nowadays is in the .357 mag/10mm range.
