I quite like the design of the English StackExchange site - I actually think it's one of the best of all of them. I only have one rather serious complaint with it though, and that's the colour of hyperlinks. I cannot pick them out of a block of text, regardless of where I view the screen from, because I am red-green colour blind (as are about 6% of the male population, according to Wikipedia).
It's rarely a problem for me, and if not for the test that involves picking numbers out of coloured circles (which I failed miserably!) I probably wouldn't even notice. Unfortunately I just can't pick the links out here though - I actually have to run the mouse over every word until I see the cursor change. I've tried on a couple of monitors and browsers with the same result. I compared this to a friend at work who can spot and point out the links from over a metre away (much to his amusement when I sat there squinting afterwards).
It's particularly annoying because I really enjoy many of the citations people use when answering some of the better questions, but it's a real struggle to locate them!