Premature ovarian insufficiency (POI) is a challenging condition that affects women’s reproductive, endocrine, and psychological health. It represents the loss of ovarian activity before the age of 40, leading to estrogen deficiency and infertility. The diagnosis carries lifelong implications that extend far beyond fertility, influencing cardiovascular, skeletal, sexual, and emotional well-being. Clinicians must be prepared to recognize POI early, confirm the diagnosis accurately, provide individualized hormone therapy, and guide women through fertility options and long-term health maintenance. This chapter outlines a comprehensive, clinically practical approach to POI based on current evidence and consensus guidelines.