Aesthetics / Decor / Spousal acceptance is the main issue. Just got the 5.1 setup up. The sub definitely needs to be out of the way of line-of-sight. I have 2 options, one is behind the entertainment center, which sits kitty-corner, but makes access to it hard and blocks sound waves, the other is next to the far end of the couch which is out of site. Haven't setteled on which I'll use yet.
Next to the couch, where the surrounds go, is a wood stove. There's brick around it, so when I watch movies I lift the left surround on top of the brick, which is ear level. I've got a thermomoter over there, making sure the fire isn't stoked up too much and getting to hot over there for the speaker. When not watching movies, it goes back on the floor.
Also, with a 2 1/2 year old running around, trying to keep her hands off the A/V receiver and such is a bit of a chore. And the TV needs to be out of sight, so it's in an entertainment center with doors that close, which limits me to a 30" TV (which I'm in the market for, btw), as long as the speakers are on the bottom of the TV and not the side. It gets the job done.