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For a full-size handgun, I like the all-metal Sigs. They are rugged, accurate as heck, reliable, and the fit and finish is always top-notch. Someday I'll get on of those P220 Stainless Elites with the wood grips--sweet...
As far as subcompacts go, the old AMT Backup in .45acp is a VERY nice gun, but since they don't make them anymore, getting them serviced, or finding spare parts is getting tough.
And of course, the Detonics Pocket 9mm was a fantastic "pocket gun" in a pretty respectable caliber. Although 9mm isn't my preferred round, the Detonics Pocket 9 makes carrying 9mm as a BUG pretty tough to argue against...
If I HAD to pick a polymer-frame full-size gun for defensive carry, it would be the Glock 20. Reliable, rugged as a brick, relatively low-maintenance, and 10mm--what's not to like?
As for "sub-caliber" handguns, the Walther P22 is the most fun pistol I've ever shot.
And I sure do miss the Grendel P12 that I owned years ago. As polymer pocket pistols go, the Grendel was VERY reliable, and fun to shoot, even if it DID kick more than my Colt Delta Elite. The fact that it fed nearly anything I put through it, and was chambered for .380 auto made for a very servicable BUG. Plus it's butt-ugly design was actually a "plus" in my book...
But if we're counting Science Fiction guns in this discussion, I think the hands-down winner for favorite semi-autos is Hans Solo's Blaster from the original Star Wars movie: