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. POI is considered as a multifactorial and heterogeneous condition with a wide spectrum of causes, such as cytogenetic, autoimmune, infectious, metabolic, or iatrogenic causes. Most women affected with isolated POI still appear sporadically, and the exact underlying pathology remains unknown. For early prediction of the risk of POI and prevention of the detrimental consequences of POI in terms of fecundity and general health, the determination of characteristics and the risk assessment of the POI population may be more important than the prediction of the prevalence of POI in the general population. POI has widespread consequences for general health and fertility. Challenges remain in the modalities of assessment and management of this complex condition. This review primarily focuses on the key questions and recommendations for clinical practice regarding the assessment and management of women diagnosed with POI. Therefore, this article provides an updated review of novel findings regarding the diagnosis and management of this challenging disease.