People often use this phrase, not as a question, but as a statement. It means "There is no difference". You say "What's the difference?" when someone is making a big deal out of preferring one thing over another, but you don't think it matters. For example, when discussing who to vote for in an election, you can respond:
What's the difference? They're all just a bunch of dishonest ego maniacs if you ask me.
When a family member is taking a long time to decide between two different types of shampoo at a store, but you're in a hurry:
What's the difference? Just pick something and let's go!
Of course, you can also ask "What's the difference?" when actually want to know what's different between things that seem the same to you. When you use "What's the difference?" in this way, it's a real question. People will be able to tell which way you're using "What's the difference?" based on the situation.