Every time someone asks this question I point them to this video
where a man empties two .22 revolvers point blank shooting at his lawyer. The lawyer lived. Is that the caliber of gun you want for self defense? Not me.
I saw a lot of people saying a .22 is a viable defense round in this thread before I stopped reading the comments. They're wrong. A .22 can certainly kill "if" you hit someone in the right spot. But hitting someone in the right spot is not nearly as easy as all that unless you're shooting at someone that isn't expecting to be shot. Most home invaders, criminal types, etc. are ready for a confrontation and won't be a sitting duck type target. That leaves you trying to hit a concealed and covered target and / or a moving target. The video tells you exactly what you need to know. The lawyer was shot in the neck and lived. I have a hard time believing that would have turned out the same if the guy had a .45. Yes you might still kill them or stop them with one shot of .22 LR. But a larger round has a MUCH better chance of doing the job you want done. That lawyer was shot FIVE times in the face and the upper body. That's exactly where you would try to shoot him. He walked away from it. No way he does that if the gun is a .45. Not a chance.
Every expert in the world will tell you this. They don't just say it for fun. It's true. I know people who were shot in the head with a .22 and the bullet followed the bone alright - right around their skull and out the other side with nothing more than a cut on his head and it wasn't even that bad. He never had the slightest problem with being shot in the head. Think about what I'm saying here. He was shot in what is considered to be the most lethal spot and he barely noticed it. It's not like his life was saved by heroic efforts at the hospital either. None of his wounds were life threatening. None.
A .22 will NOT do the damage of a larger caliber weapon like a .45 or a 9mm or a .40 caliber. It certainly won't do the damage of a centerfire rifle caliber from a .223 on up. It's not even close.
And the idea of shooting multiple shots means you need to make multiple hits. The odds of that happening are slim. Remember Black Hawk Down? Those bad guys were being shot with .223 rounds and they kept on fighting because they were so stoned they didn't know they were hurt bad. Most people in a gun battle will quit when they see they are seriously hurt. They don't want to die. But drunks in a stupor, PCP blasted dopers, crack heads, etc. are often going to be just like those khat heads in Somalia. They won't even realize they're shot until you hit something vital that puts them down.
If you want to be a hit man then yes a .22 can work well for you. If you want something to defend yourself and your family get a centerfire weapon with as much power as you can handle.
There's a reason you don't see armies using .22's. Yes I know about how Israel used them to take out guards quietly. But that's one very limited example. If they were actually good for SD you'd see at least one country using them in their army. But no country does.
I guess the question is "why" would you choose a .22 for self defense when clearly other calibers are far, far superior? It makes no sense to me at all.