i cut all of my button holes in my plexiglass with a dremel, it took a little while, but worked well. i havent tried making really small holes, like those needed for a usb port though. i just clamped my plexi to a piece of wood to hold it steady and keep it from flexing. i used a high speed cutting bit. i drilled a pilot hole with a drill, (big enough for the dremmel bit to fit inside) then just let the dremel do the cutting. i have a low end dremel that only has one speed...fast, so i don't know what would happen at slower speeds, but at high speed, it pretty much just melts through the plexi leaving a nice hole. the reinforced cutting disks do a nice job on plexi as well, if you need a bigger hole.
the best part about plexi is how wonderful it looks when the back side is spraypainted black. i used $.98 flat black spraypaint from wallmart on the back of my plexi bezel, and i am very pleased with how it turned out. it looks very glossy.