In real estate, the mantra is "location, location, location. In self defense, it should be "shot placement, shot placement, shot placement". Over the years, I've been asked several times what caliber and/or gun is best for defense. At home, I recommend a shotgun, especially if it involves people who aren't going to train extensively with a pistol. For carry, I'll often recommend pepper spray, or now that they are legal here, tasers if the person asking isn't willing to spend time practicing. If they are willing to spend time practicing, then I tell them whatever caliber and style of gun feels best to them. Sounds to some like a cop out, but I firmly believe that an 80 year old great grandmother with a .22 pistol she has shot so much it's become a part of her is far better equipped than a 30 year old with a 45 acp he's never fired.
BTW: From what I've read, assassins prefer silenced .22 pistols for a few reasons. Very little noise, and while the will easily penetrate the skull, it usually won't exit, instead ricocheting around inside and playing havoc with brain tissue no one could survive.