For me, it's a tossup between two. My family wasn't into guns, so I don't have any family heirlooms to brag about.
The first is my Glock 21. Except for when I first started in LE with a Sig 226, and a brief and disastrous flirtation with the .40 S&W round in a G23, my G21 has been my duty gun since I bought it in '92 or '93. We have been through a lot together and it has helped me out through some tough scrapes, although it hasn't had to speak in anger yet. It has over 30,000 rds through it and, aside from some of my reloads that weren't properly sized when I started reloading and a mag with a bad spring, it has been utterly flawless. I know it inside and out, upside down and right side up, forwards and backwards, you name it. When we hear a "bump in the night", the G21 is what I grab.
The second is my 2 1/4" SP101. It is my backup weapon when on duty and is my off-duty gun. I've only had it for 2 or 3 years but it has also proven itself to me to be utterly reliable. Like the G21, it has helped me out of a few tough scrapes but, also like the G21, has never had to speak in anger. It is a comforting presence when we go somewhere and see someone I have arrested in the past and gives you "the look" or if you see someone who makes your internal radar go off.
I have quite a few others that I like quite a lot, but those two are my favorites. I don't know what I'm going to do when the G21 finally gives up the ghost. I just can't see myself carrying anything else, even another G21. Both guns are quite "plain" compared to some here, but I love them.
Bub