I set up mine where my mod wheel controls velocity xfade, and the XY axis' of the matrix are controlled by keyswitches.
My up/down moves are controlled by black keys, then the white keys in the same region control the left/right movements. I organize the patches in terms of how similar or dissimilar the articulations are. For example, all of my short ones are in one row, legatos in another, harmonics plus trems in another, etc.
I'm a pianist, so that black key/white key set up is very natural for me to maneuver.
To switch to additional matricies, I also use key switches.