Statements that are independent of ZFC are a dime a dozen when doing foundations of mathematics, but they're not so common in many other areas of math. Harvey Friedman has done interesting work on finding "natural" statements that are independent of ZFC, but there's dispute about how natural they are. https://mathoverflow.net/questions/1924/what-are-some-reason...
In fact, it turns out that a huge amount of mathematics does not even require set theory, it is just a habit for mathematicians to work in set theory. https://en.wikipedia.org/wiki/Reverse_mathematics.