Whenever I am downtown, I stop at the Tattered Cover, and I rarely come away empty-handed. They have a great selection, are housed in a big old building with loads of character, and the people working there know books. There are lots of nooks where you can tuck yourself away with your books and read for a while, undisturbed, as you choose which books you will purchase. The coffee bar is excellent as well, and (important to me!) they don't charge extra for soy. I've also been to events there, which makes the Tattered Cover a real community place.
PROS: Location, books, staff, coffee bar