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Asks what another has his attention on. What is he thinking about or busy with? "Up" in this case is using a slang definition from around the 1930s meaning: occupied with, busy with.

This question is often used to start conversations with.
When I called my friend he didn't seem happy so I asked him "What is up?". He said he was having trouble with his girl.
by Scottmana September 15, 2007
The way you greet a friend when you are feeling a little bit retro and a little bit geeky.
What is up my brother?
by Anonymous August 18, 2003