Primary ovarian insufficiency (POI), a clinical syndrome, is defined by the exhaustion of the functional potential of ovaries prior to 40 years. The consequences of POI are potentially serious for long-term fertility, reproductive health, and general health because of early menopause. This article provides an updated review of different etiologic factors and pathogenic mechanisms that lie behind POI as well as current and novel strategies for the management of this challenging disease aimed at the primary prevention of the adverse effects of estrogen deficiency and infertility related to the early loss of ovarian function.