An open problem in algebraic topology is whether arbitrary cohomological localizations of simplicial sets (or, equivalently, topological spaces) can be proven to exist in ZFC. It's provable in ZFC that arbitrary homological localizations exist, but for cohomological localizations I believe the best result is that they follow from the existence of a proper class of supercompact cardinals. (In particular, they follow from Vopenka's principle, but according to BCMR "Definable orthogonality classes in accessible categories are small", a proper class of supercompacts is enough since the class of cohomology equivalences is $\Sigma_2$.)
I would like to know how important this open problem is. Are there other open problems that could be solved if cohomological localizations existed? Have any important theorems been proven using cohomological localizations assuming the appropriate large-cardinal hypotheses for their existence? Are there particular cohomology theories that we would like to localize at for particular applications, but we don't know how to do so without large cardinals? Or is the open problem of mainly theoretical interest (e.g. perhaps most cohomology theories arising in practice can be localized at using less general techniques)?