Primary ovarian insufficiency (POI) is an uncommon yet devastating occurrence that results from a premature depletion of the ovarian pool of primordial follicles. Our understanding of both putative and plausible mechanisms underlying POI, previously considered to be largely “idiopathic”, has been furthered over the past several years, largely due to advances in the field of genetics and through expansion of translational models for experimental research. In this review, our goal is to familiarize the multidisciplinary readers of the F1000 platform with the strides made in the field of reproductive medicine that hold both preventative and therapeutic implications for those women who are at risk for or who have POI.