Several guns I own have a sentimental appeal and would be the last I'd get rid of, and some have collector appeal for me, but from a purely practical stand point, I might be able to narrow it down to two. The most practical thing that I personally can do with a handgun is protect myself and defend my family and property, so conceal carry would have to be the genre of handgun that I'd choose from. I think I have to admit to myself that my LCP is the carry-able gun I own. It's a rare moment that I'm not carrying it. That's a pattern that's never changed much in the years I've owned it. I'll carry a J frame for a while, or a small 9mm, but I go back to the LCP because it's so convenient.
If I can have two guns, then I'd have to have another for the times when .380 just isn't enough - when walking or spending time in the outdoors, for example. I prefer to stay within the realm of concealed carry, so I think maybe my Rossi M720 (like the one in my avatar) from the Interarms era would be a logical choice. I can conceal it pretty well, but with .44 Special ammo from Grizzly or BB, it could handle many wildlife threats. Some possible alternatives to it would be another Rossi just like it that's chambered in .357 that would give me an extra round, or maybe the recent Charter Arms .41 Magnum I picked up, but that will take more practice to control it for optimum effectiveness.
Though the M13 Smith and Wesson I own has a longer (4") bbl that would make it less convenient to carry, it's an extremely accurate gun, and would get more velocity from the longer bbl, so that's a possibility, too. (It's a well known .357 revolver in the K frame size.)