It can be used as a casual greeting, but as a question to start a light conversation, it basically means "what's news?"
If it turns up late in the conversation, it can mean concern, as SineWaves put it. For example, we've been talking and I notice you're unhappy but you haven't said why. "What's up?" I ask.
It's not a phrase to use with people you don't know well. If it's not used with close friends, it sounds if as the speaker is being too familiar and presumptuous.