There are a few ways you can use this. The first way is to mean "Is there anything new or exciting happening in your life?" This is often used as a kind of greeting, but usually as "What's up?" The second way is "Why are you acting differently than normal?" If your friend was being very rude to you when they are normally friendly, you might ask "What's up with you?"

We use "What's up?" in a casual way (with friends) to ask 'what's new in your life' or 'what's going on in your life'. A conversation could go like this; Wik: Hey Elena! What's up?" Elena: "Hi Wik, not much at all.. I have been busy with my studies. What's up with you?" Wik: "Same, not much. Just the same old." "What's up with you?" can also be used in a way of asking "What's wrong with you?"