I can't really argue with most of the choices I see here. I personally think a 4 or 6 inch .357 magnum is the optimum defense gun, but only by tiny percentages.
The real advantage of the .22 is that it is so much fun to shoot. That and the fact that one can shoot all day without going broke.
I grew up on a farm and was lucky enough to have a Father who was a shooter. I remember him killing hogs and steers with a .22 rifle. They would drop like they were pole axed.
One of my favorite writers was Russel Annabel. He once wrote a paean to the .22.
Living in Alaska from the early part of the 20th century, he kept a Colt Woodsman with him all the time. He recounted story after story of how the the Woodsman saved his hide. He ended the story by saying they should build a monument to the .22.
Of shotguns, I would choose a Remington 11-87, but the Winchester model 1300 defender is a better buy. The 870 is simply the best pump ever including the model 12.
Concur completely. Additionally, you can get in a decent amount of practice and not bang the heck out of yourself. I love my Glock model 22 in .40 S&W, recommended above, but I find that after about 200 rounds my hand buzzes - I use a weightlifter's glove if I'm going any distance with that gun. Conversely, my Kimber (1911-style .45ACP), which to my grip is more ergonomic than the Glock, can go 300+ rounds without making me ache.
But shooting those guns is like throwing quarters downrange - it's less if you reload, but it's still significant. You can buy a brick (500) of .22 ammo for $12-15 and practice all day. And with practice, quantity and quality BOTH count.
As for self-defense, though, the .22 is simply inadequate even if you are a very good shot. A strike to the head isn't necessarily fatal - records abound of the bullet glancing off the bone and even entering the cranial cavity, following the skull around, and stopping inside without killing (although it'd sure get the perp's attention). The only sure target is the orbit of the eye, not always available, and try to hit THAT in a semilit room on a moving target!
There isn't really a perfect indoor caliber - anything small enough to not penetrate wallboard (and a Glaser WILL penetrate wallboard, contrary to the above - I proved it to myself) may not penetrate heavy clothing, and anything big enough to knock down a perp is big enough to go through a wall. Indoors no shotshell, even #9, will disperse enough not to have the same problem - at 15 feet even the fine birdshot is still a lump about the size of a slug, and with nearly that hitting power. Each caliber, and each shooter, has a compromise that is unique to the individual.