My argument is regarding, note here; CIVILIAN PERSONAL DEFENSE (not police, military, or defense agains bears or rhinos):
First: We should all agree that the weapon we have with us all the time as a civilian, is senior to the one we don't have when it's needed. A person therefore who decides to carry a firearm full-time will more likely carry a smaller lighter gun more of the time... than the same person will carry a larger heavier gun.
Second: For many folks concealment is difficult in MANY situations. Not everyone can wear baggy clothing with the shirt tail out and a vest or coat all the time. The .22 pocket pistol can be concealed almost all the time; no matter what one is wearing. One of my old clients (a "wet" agent for the US Govt.) used to carry a Walther TPH even when he wore his Speedo swimming suit. In that situation he pushed it into two condoms, one within the other and secreted it "up tight and out of sight". By the way this same professional, whose jobe was personel removal, had two larger guns for his job; a .22 caliber Ruger Mark 1 and a .22 caliber AR-7 Explorer.
Third: If one has to fire a handgun in self defense; shot placement is paramount to any other factor after the factor of "having it with you". There are many .22 pocket pistols that are more accurate than most larger calibers; until you get to 9x18, 9x19 or .45. I agree here that before the advent of the super .22 such as Aquila, Stinger and especially Quick-Shock that the .32 was superior in power and equal in accuracy. The .25 is not more powerful and is not any longer any more reliable according to my experience.
Fourth: In the "old days" it was often enough to show your gun when needed; in that situation a Desert Eagle or a 10 gauge double barrel is nice to pull; that is NOT a good idea anymore. Once the firearm is pulled out (brandished the prosecuting attorney will say) you are at severe risk of going to court whether or not you fire. So it is NOT a good idea to pull your gun to stop the fight any more unless you are on-duty law enforcement. The .22 pocket pistol can be gotten to and pulled out ready to use, or kept where it doesn't show and with your hand on it and finger ready for the trigger, until time to draw and fire. That readiness is far more difficult to achieve with any other caliber.
Fifth: The .22 can be fired in practice far more affordably than any other caliber. With extensive practice, which is most sensible if one decides to carry a weapon; the draw and shot are improved.
Sixth: The old arguments about power, reliability and effectiveness of the .22 are lessened dramatically when the discussion of the pocket .22 for defense includes; that the tiny pistol will be loaded with Aquilia, Stinger or BEST of all... Quick-Shock.
The Quick-Shock is tremendously effective in a water saturated and somewhat confined media; such as a living meat body. Those who doubt the effectiveness of the Quick-Shock should do a test and take several pistols of different calibers out and test them on cheaply available large vegetables and melons, # 10 cans of tomato paste or beef stew, or out of date meat from the grocer or butcher. In fact, as I was becoming a believer I decided to try the Quick-Shock out on a large ham... Scary!!! Not much left to eat... Better yet try one on some living animal that needs killing for food or to eliminate a feral threat (legally I hope).
When my son and I tested the Quick-Shocks against even the "best" larger and more expensive calibers on numerous hydroshockable media we decided in favor of the .22 Quick-Shock. Try it yourself before you take me on with this argument please. I know I've seen the ballistic gelatin tests claiming that the Quick-Shock is not effective. I also am personally aware of tests on numerous tests which included large cabbage, pumpkins, melons, pigs, cows, feral dogs, diseased fox, and some more... no I don't know of any tests on humans and won't likely either. Those folks who use .22s on humans, and there are some who do this as a job, don't talk to me about such things.
OK... I agree... Bigger is better... when available. When I was younger (40 years ago) and the relevant law was not enforced; I carried an over and under 12 gauge sawn down to nearly pistol size (11" end to end). And when I lived, walked and camped in the swamps of central Florida 20 years ago, I carried a very short and legally modified pump 12 gauge 4 shot which was sawn at the end of the magazine tube and just behind my right pinkie when I held the trigger. So if we are going to talk pistol caliber for stopping power -- sure... 12 gauge, 10 gauge, or best of all a VERY (flare signal) Pistol are better; they can be had for a price. But will it qualify as "always with you" per my first argument above?