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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!
by Cinymin86 November 16, 2009
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One of the funniest series of sketches Saturday Night Live have ever made.
Seriously search "Whats up with that snl" on Youtube
Kenan Thompson "Ooooh yeah, Whats up up with that, whats up with that"
via giphy
by Naughtopus June 11, 2018
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