Flexbox already fixed the biggest issue I had with CSS and that was the complexity associated with building simple box-based layouts. There are still things that can be made simpler - things that are used every day.
Standards standards and standards - thing are a lot better these days compared to the IE6 days where IE6 didn't even follow the standard BOX model (see here for more info), but you still have browser specific prefixes which are annoying.
Arithmetic would be nice to have, for example, if I say height: 100% - 10px, I want my div to be 100% parent div minus 10 pixels for example. Some other things I'd like to see as well is height: 100% x screenheight - 10px, currently it's quite a mission make use of %-based heights.