Now, with all of the calibers and weapons choices available today, I know I've left out a lot that are in vogue, and are undoubtedly many people's favorites. But by looking at realistic scenarios and practical applications, I will explain why I feel these particular calibers are the best for close encounter defense.
In a close attack situation, it is imperative that the attacker be incapacitated immediately. This results from one thing; critical tissue damage. By this, I mean incapacitating damage to tissue that is critical to the continued function of the body or bodies of those posing a threat. This does not necessarily equate with being fatal. A wound that will prove fatal within an hour or two may not do sufficient immediate damage to an attacker to force their immediate cessation of threatening behavior. For instance, if you stuck an ice pick through an attacker's shoulder and nicked the brachial artery, they would still be able to continue an attack, though they might bleed to death a few hours later. However, if you separated their shoulder (knocking the humerus from the glenoid capsule of the scapula) with an ax, they would most probably not be able to continue the attack, though they would not necessarily die.
For this reason, the cartridge (and I say cartridge, not caliber) is of primary importance, as it will determine the three most important factors in close encounter self defense situations; immediate debilitating tissue damage, handling (controllability, particularly on the second and subsequent shots), and collateral safety (making sure expended rounds don't exit the target or area to cause beyond-target casualties.
With these factors in mind, let's look at the most common handgun calibers.
.22 caliber: The .22 comes in four basic loads; short, long, long rifle and magnum. While some professional assassins have liked the .22 magnum used in a particular weapon (no need to go into detail), and some military and para-military survival kits have included silenced varieties in order to facilitate the taking of small game with minimal noise, the .22 is best used for squirrels, rabbits, paper targets, and plinking tin cans off of fence posts. If you try to use one for self defense, I would suggest you shoot yourself in the foot in hopes of making your attacker die laughing.
.25 caliber: Ian Fleming's original arming of his fictional James Bond with a .25 caliber automatic was undoubtedly the result of Fleming's limited understanding of field necessities, and a British Naval aversion to ruining the line of a Saville Row suit. When he was finally brought to his senses, no doubt by someone who knew better, he had his fictional "Q" provide his fictional "Bond" with a .380 Walther PPK, calling the .25 "worthless". Well, he got it half right.
In the non-fictional world, a .25 is known as the weapon of choice of light-weight women and pimps, primarily because it can easily fit in a handbag for the women, and a shoe or sock for the pimps. It is not carried by anyone who is actually ready and willing to use a gun, and knows anything about them. Real world use for a .25: plinking cans off of fence posts from six feet away, or, with blanks, starting a foot race.
.380 caliber: Nominally better than a .25, a .380 can stop an assailant if it enters the brain through an eye or ear, the roof of the mouth, or punctures a carotid artery or severs the spinal cord (just like a .22 or .25). Otherwise, a strong man can easily carry the entire clip of rounds you just put in him as he brings it home to you. Real world use for a .380: target practice, or as a fourth back-up weapon.
.38 caliber: Coming in different factory loads, including "Special", "+P" and "Super", the .38 was standard issue for American police and certain military units for decades, even though its limitations had long been known. Marginally effective with hollow-point ammo, you may still have a fight on your hands after depositing a few in a determined assailant. Though I carried one when required, I thought of it mostly as a part of the uniform, and it was never the weapon I depended on.
9mm: Made popular by New York narc Frank Serpico, and the subsequent book and movie about him, the 9mm Browning Hi Power became the pistol de jour because of its 14 round magazine. This, combined with the fact that it became the standard NATO cartridge, caused the 9mm to become the most widely heralded and desired weapon around. This image has been carried forward to today's self-imagined "gangsters" who like to hold their pistols sideways and say things like "Get my 9". Its reputation exceeds its capabilities, however, as the design and load of the 9mm causes it to pass through soft tissue with minimal shock or tissue damage. It's a good thing high capacity magazines were a hallmark of 9mm pistols, as more shots were often needed to down an weapon - never as my primary.
.357 Magnum: Anything with the word "magnum" in it sounds scary, and scary reputations are carried on and built up by the repeated stories told about them - usually by people who don't know what they are talking about. While the .357 magnum is an excellent cartridge, it also has its drawbacks. Essentially a .38 long, the .357 gets its power (shock energy) from its high velocity load, which exceeds the .38 by anywhere from 400 to 600 fps (feet per second) muzzle velocity. This power, which can cause substantial tissue damage, can also cause bullets to pass through the intended target and cause beyond-target casualties. There is no reason to "load it down" to decrease the velocity, as what you would have would essentially be a .38.
.44 caliber: Made famous by Clint Eastwood's "Dirty Harry" in the early 70's as "The most powerful handgun in the world", the .44 magnum is an excellent cartridge for hunting elephant, rhino, bear, water buffalo and other large game, driving railroad spikes from a helicopter or stopping a car. However, it's not the best for personal close encounter defense. It will tear a person up - there's no doubt about that, but the high velocity cartridge makes it a poor choice for personal or home defense where beyond-target casualties are possible. Also, its weight and recoil make it difficult to handle for anyone who doesn't regularly train with one.
A .44 Special is a better choice, as it maintains the size of the slug while slowing down the delivery to an appreciable degree, thereby guarding against over-penetration. If using a magnum weapon, ammunition can be slow-loaded (loaded down) to about 850 fps for maximal efficiency. Revolvers can be loaded with soft-lead semi-wadcutters (with some other added tricks), resulting in maximal stopping capability. This cannot be done with autos, which would jam with such a cartridge.
.45 caliber: This is my choice of handgun for personal and home protection. The .45 is a man-stopper, pure and simple. The size of its slug, combined with its comparatively slow standard-load muzzle velocity, ensures that whatever it hits is going to be torn up, torn off or knocked down. This is of primary importance in a self or home defense situation, where immediate incapacitation is imperative. Take someone in the arm, shoulder, torso, hip, thigh or knee with a .45, and odds are heavily against their being able to continue any kind of coherent, directed attack. The relative low velocity, combined with the mass of the slug, minimizes the risk of the slug passing through the target and causing beyond-target casualties.
During my years undercover, with CSOG, and other assignments, a .45 Colt Combat Commander was my primary handgun, and the .45 auto remains my tactical choice today. There are a number of manufacturers that produce high quality .45 autos today ( I recommend autos over revolvers for ease and speed of reloading, as well as compact design), and the choice can be pretty much be made according to hand size, "feel", and preference for single or double action. The noise and recoil of a .45 can be intimidating to anyone who is new to shooting large caliber handguns, but one should put a good deal of practice into any weapon they may have to use, and practice will overcome any initial problems. Also, the muzzle flash from a .45 is substantial, which is helpful in lining up second and subsequent shots in dark environments.
.50 caliber: The Israeli made Magnum Research Desert Eagle .50 caliber auto is probably the grandaddy of all handguns right now, and I have yet to meet anyone who has carried one who didn't like it. However, the cost can be prohibitive (upwards of $1300), and if you have to pay for your own ammo, you'll go broke before you get really good with it.
10mm & .40 caliber: These are comparatively new entries to the market, and have been marketed specifically to law enforcement and military (the largest bulk purchasers). Each have their fans, though I have not met anyone who feels they are a measurable improvement on existing calibers. To me, they fall within the range of the marginal calibers discussed.
Best pick for personal and home protection: .45 auto