The two things that matter the most: that it "fit" you, and that it be reliable.
My HK USP Compact 9mm is the most reliable handgun I've encountered and certainly is heads, shoulders, and beltline above my SIG P220ST and S&W 1911 in terms of reliability. It's not the easiest for me to shoot well, but it's very accurate to boot.
Put a lot of guns into your hands and shoot as many as possible. Chances are the best gun to fit your hands will meet the reliability requirements if it says HK, SIG, CZ, Ruger, Walther, Springfield Armory, Glock, Kahr, Browning, FN, Smith and Wesson, Beretta, Steyr, Taurus, IMI/Magnum Research, Star, Kel-Tec, etc..
Just stay away from Hi Point, Lorcin, Raven, Jennings, and other low-dollar pot metal guns.
Once you've chosen a gun, ask here what people think about it. For instance, Someone might suggest that you need a reversable magazine release, light rail, or that you should choose a DAO gun. There are a myriad of configurations.
Of course, I'm making certain assumptions: that you would be using it for the range and for home defense duty. Requirements change depending on usage: HD guns benefit from night sights, range guns benefit from high-contrast sights; House guns are better fullsize, small guns are often preferred for concealed carry.