Once formed, the pool of dormant primordial follicles serves as the source of developing follicles and fertilizable ova for the duration of a female’s reproductive life. Depending upon the species, primordial follicles can remain quiescent for months, years, or even decades, and the highly regulated process of primordial follicle activation ensures the availability of growing follicles throughout the reproductive period. We have recently begun to elucidate the molecular mechanisms underlying the maintenance of follicular quiescence and the activation of primordial follicles, mainly through the use of genetically modified mouse models. Both overactivation as well as the failure of activation of primordial follicles can lead to pathological conditions such as premature ovarian failure (POF) in the experimental models. A thorough understanding of the underlying mechanisms that regulate quiescence and activation of oocyte growth in primordial follicles will have important biological and clinical implications.