I made a lot of progress on my first enclosed system yesterday, thanks again for all the tips. The key for me was going with two pcb's, one for the top panel to connect the display, buttons, led's and other stuff that comprises the interface, and a separate panel for the main board, connected by a ribbon cable. Then, using bare prototype board to physically simulate the PCB and drilling holes so I could mount it under the top of the enclosure. From there, everything fell into place. Now I (almost) have a fully-built unit with no actual electronic connections. Yay.
Next thing I'm going to try is drawing to the milling layer in Eagle, and spitting that out as an EPS during the CAM job. With an EPS I can do a laser-cut acrylic at Metrix Create Space. That'll serve as a prototype of the panels, so I can see that everything is lined up nicely with CAD-specified cuts. Then I'll have to figure out where in Seattle I can do the actual milling of the case. (Metrix won't laser cut ABS).
Yenka looks super cool, but not ready to spend the $$ until exhausting all free options.