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Ask 100 gun-owners this question and you'll probably get 100 answers, so here's my long-winded $0.02.
If you want the short version, get a 3" (if you conceal more often) to 4" (if you carry open more often)barreled .45 auto or a .357 magnum and just take my word for it.
If you want the logic behind that statement, read on.
Personally I feel that .380 auto is the absolute minimum for terminal performance and even then only if you have excellent shot placement and often times multiple rounds into the target. The .380 auto only generates about 200 ft-lb of energy at the muzzle. The .25 auto and .32 auto really aren't worth considering at all unless you're after an ultra-concealable pocket-gun. The .25 auto only puts out 100 ft-lb of energy and the .32 auto only puts out 128 ft-lb at the muzzle.The9x19 Parabellum (Luger, or just 9mm) generates 360 ft-lb of energy is a decent performer, but there is some argument that the wound channel from a 9mm is often inadequate. If you ever had to fire your M9 in combat while serving the Army you can relate to people's lack of trust in the cartridge. The .40 S&W is better, delivering480 ft-lb of energy at the muzzle, which is definitely good for terminal performance, but in my experience, most .40 smiths have a very snappy, sharp recoil and this can lead to control problems in less experienced shooters. The .40 smith is not much bigger than the 9mm in terms of diameter, but because of the increased velocity and bullet weight, the terminal performance is quite a bit better.
The king of the autos (within reasonable cartridges for a carry gun) is the .45 ACP, which is a nice, wide, heavy bullet delivering just over460 ft-lb(edited) of energy with good self defense ammo. There really isn't much better out there. For a practical carry auto the .45 is hard to beat.
Don't overlook revolvers though. They're more reliable than an auto and arguably safer as well. (Not to imply that autos are unreliable or unsafe, but revolvers are a small amount more reliable and safe.) They do have a reduced capacity and are a bit thicker so concealment and carry comfort may suffer. (Yes, I know this is an open carry forum, but concealment should be considered when purchasing a handgun.) The .357 Magnum delivers 540 to644 ft-lb of energy and is a proven performer. It's considered to be one of the most lethal cartridges in use. The downside to the .357 mag is that the recoil can bequite strong andthe cartridge really doesn't perform up to its potential in shorter revolvers,like the little snubbies that are so popular. Many argue that shooting .38 Special +P or +P+ ammo in the sub-2" barrels is identical to shooting .357 Magnum from the same barrel, but with less recoil. The .38 Special +P+ ammo is supposed to get around 260 ft-lb of energy.
There's a new cartridge called the .327 Federal Magnum and Ruger makes a compact revolver chambered for it called the SP101. Barrel lengths are 2-1/4", 3-1/16" or 4" and they claim that it delivers equal terminal performance to the .357 magnum with much less recoil. The .327 FM gets about 430 ft-lb of energy and that's definitely worth considering, although I haven't personally fired any revolvers chambered for it. The nice thing about the .327 SP101 is that it gives you a full 6 shots in the cylinder, vice the 5 that most of the compact revolvers have. (The SP101 chambered in .357 mag is a 5 shot cylinder.)
As far as I'm concerned, a nice shortened frame 1911 style .45 autowith a 3" barrel or a compact revolver chambered in .357 Mag (or perhaps .327 Federal Mag) with a 3" barrel is ideal. I'm not a big fan of the sub-2" barrel revolvers because they have too much muzzle flash, are not very controllable or accurate, and aren't very efficient in terms of energy actually delivered to the target. I think the 3" barrel is an ideal compromise between portability and concealability vs.accuracy, controllability, andefficiency.
I would love to get one of the Kimber Ultra Carry II in .45 ACP (7+1 mag), but I can't justify the expense right now. The Smith J-Frame with a 3" barrel in .357 mag is what I carry. I lose 3 shots, but I have the ultimate in reliability and just a tad more energy delivered. The Ruger SP101 in .327 would be fun to get, but it would fill an identical niche to what I already use and only give me one extra round. It's not worth the expense, even though the SP101 is muchless expensivethan a comparable Smith and also much less expensive than the Kimber. (There are other .45 options available: Taurus, Para-Ordnance, HK, Sig, Springfield, Smith, etc)
The threegunsI chose are based on a pistol I would carry concealed more often than open. (I know, I know, open carry forum...) If I was getting a strictly open carry gun, I'd love to get an HK Mk 23.
(I don't mentionthe .44 mag, .460 smith, .480 ruger, .454 casull, and .500 smith even though theyare much better terminalperformers because they're ridiculously impractical to carry in most cases and the recoil is very stout. The .50 American Express, which the Desert Eagle fires generates over 1200 ft-lb of energy, but it's a ridiculously large gun to carry and the recoil is again, on the ridiculous side for a defense application.)
The guns are a little pricey.