I love the system in Autodesk Animator (now: https://github.com/AnimatorPro). Every menu item or button currently on the screen always have a unique initial letter. There is no need to highlight or underline anything. Amazingly this was done without having to use any too obscure labels (but I doubt it would be fun to try to translate it to other languages). Almost every function is two or three single letter key-presses away, and after using the application for a while you will have memorized more and more of those.

Some frequently used functions have their own special single-key shortcuts as well, so instead of having to press C-P (to open the Clip menu and then select Paste) you can just press the ' key, saving the user a key-press every time they do that.