The two biggest issues I come across regularly is icons people don't understand the meaning of, and the fact that the UI changes frequently. I've found a lot of the people I work with learn how to do things, and then expect them to remain that way. Moving a button over two inches or putting it in a menu will send people calling me to come back because they don't know how to do something.

I have a lot of people literally ask me to repeat a process several times so they can write each step in doing things like attaching a file or forwarding an email down on paper. So when a button gets renamed or moved or even just has an icon instead of text, it throws people.