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I have 208hp x 12u set up in a half horizontal/half vertical layout (picture 4 Mantis cases with brackets or something similar). I keep sequencing, mixing, and controllers in the front, with oscillators and filters at the top, signal flow mostly left-to-right. Most of the time I am sitting while patching, so this works well for me. I have been constantly tweaking and reworking my layout for two years, and have arrived at something that is almost exactly what I had hoped for. My muscle memory knows exactly where to reach now. It all makes sense to me, which is ultimately all that really matters.
As far as module ergonomics, I prefer large-ish modules with minimal menu-diving and button combos. Kind of a WYSIWYG interface for the most part, as I like to work fast. I've eliminated most of the modules that I just didn't enjoy using, and finally arrived at a rack size, layout, and module selection that has eliminated any serious GAS. I just can't think of much else I would ever want or need.
How about you?