I've just used SASS for the first time on a project and I ended up with a bit of a hybrid solution.
I had one main.css stylesheet which was generated by Compass (for all the SASS goodness). This just overwrites the EE CSS template when it generates.
I then had a second stylesheet dynamic.css which was used purely for stuff which the client could edit, such as background images, colours etc. This was a standard EE CSS template. The second dynamic one was pretty sparse, literally only containing the stuff that could be edited and nothing more.
I kept the two files in the location in the EE file structure for no other reason than, if someone was to follow behind me, that's where they'd expect them to be.
Splitting the stylesheets out into two separate ones might be a bit much for most folks, but I get really twitchy when working on massive all encompassing files which have loads of different stuff going off in them. I'd much rather keep things in there own separate box, and then combine them at the end. Which thanks to Natetronn is what Minimee looks like it's going to do for me.
I would be interested to hear if this is a totally dumb way of going about things as it is the first time I've done it, so I'm all ears if there is a much better way.