Formal:
* Que se passe-t-il? (This is the most common and formal way to ask)
Informal:
* Qu'est-ce qui se passe? (This is a more casual way to ask)
* C'est quoi? (This is very informal and translates roughly to "What's up?")
* Quoi de neuf? (This means "What's new?" and is another casual way to ask)
Other options:
* Que se fait-il? (This is another formal option, although less common)
* Quel est le problème? (This means "What's the problem?" and is a good choice if something seems wrong)
The best choice will depend on the situation and who you are talking to.