LEO, I'm a LE Firearms instructor so back me up here if you agree...¬*
Center mass is your best bet, largest target, largest concentration of vital organs.
In a defense situation fine motor skills deteriorate so also learn to instinctively shoot, ie-point and squeeze the trigger.¬* Most defensive situations occur under 7 yards or so, so a fist size knot of shots at 25 yards usually isn't required.¬* Also, the old addage a slower hit is better that a fast miss always holds true, plus if you miss your intended target, ie-the threat, where is that round going to end up?¬* The wall? An innocent bystanders kidney?¬* It's a HUGE responsibility.
On the subject of caliber, I don't offer any advice on size... shoot the gun you shoot best, be it a .45 or a .380.¬* Shooting a comfortable handgun you shoot well is the most important factor I can think of in a defensive situation when you have choice of what gun you'll carry.
When confronting multiple assailants, "Border House Rules" apply, that is everyone gets first before anyone gets seconds.
And on an outside note, when you become proficient with your sidearm, if center mass isn't working on an assailant, the pelvic girdle works wonders for putting someone down.