This came from the cartoon Bugs Bunny. The rabbit would always say, "What's up Doc?" Over the years, people adopted this and shortened it to "What's up?". In addition to what Emily and Saaqqa wrote, this also less commonly means, "What's happening?" Such as if we know a friend Benjamin is not coming to class anymore, we might ask our friend, "What's up with Benjamin not coming to class anymore?"

1. yo, what's up,dude?...咋样啊?...过得如何? 2. What is up with the whole world...这里what's up表示发生什么了 大致等于 what's the matter? What's wrong?

感觉这个词就像中国人见到好朋友问 ‘在干啥呢！’ 一样