Despite the advances with CSS3, we're still working with a layout engine that was designed for documents rather than applications (mobile and otherwise), so many seemingly trivial tasks (e.g. centering and vertical alignment) involve an unintuitive mess that I after 10+ years of experience, I still need to lookup from time to time. [Edit: I should have been more clear--I'm referring to issues that flexbox doesn't resolve such as aligning/sizing elements relative to each other rather than to their parents.]
On top of that, we're seriously in need of better tooling. It feels like we've spend the past 10 years developing a set of powerful primitives but ignored building tools that truly empower our creativity on the web. Sometimes I really miss how fun and simple it was to use Flash to build things when I was a kid...
...and that's the whole point really, isn't it?