A phrase used to ask about
something odd, or what the point of
something is. The word "that" can also be replaced with whatever noun
the person is asking about. It is also common to inerject the word "fuck" into the phrase to express shock or discust.
What's up with the smirk?
Look at all those bags on the road.
What's up with that?
Person1: What the fuck's up with your hand!?
Person2: Ahh! Why are you just standing there?! Take me to
the fucking hospital!