Wow - this was a really tough call for me. I'm going to go ahead and say G22, with the 17 very close behind or almost on par. I find the frame size of either to be perfect for "all around" use. Looking at stopping power between the 9 and .40, .40 has a good track record, but that said I would take no issue in choosing 9 with a premium defense load, and with 18-20 (with +2 ext.) rds on deck, you'll stay in the fight and have plenty of ammo to get the job done . As for the 21, it is definitely a brick and for me gets edged out in how it handles vs. the "standard" Glock frame seen in the 17 and 22. I can shoot mine well - just not quite as well as my 22.