Primary ovarian insufficiency describes a spectrum of declining ovarian function and reduced fecundity due to a premature decrease in initial follicle number, an increase in follicle destruction, or poor follicular response to gonadotropins. The sequelae of primary ovarian insufficiency include vasomotor symptoms, urogenital atrophy, osteoporosis and fracture, cardiovascular disease, and increased all-cause mortality. In women with primary ovarian insufficiency, systemic hormone therapy (HT) is an effective approach to treat the symptoms of hypoestrogenism and mitigate long-term health risks if there are no contraindications to treatment. Hormone therapy is indicated to reduce the risk of osteoporosis, cardiovascular disease, and urogenital atrophy and to improve the quality of life of women with primary ovarian insufficiency. Although exogenous estrogen replacement is recommended for women with primary ovarian insufficiency, data comparing various hormonal regimens for disease prevention, symptom amelioration, and safety are lacking in this population. As a first-line approach, HT (either orally or transdermally) that achieves replacement levels of estrogen is recommended. Combined hormonal contraceptives prevent ovulation and pregnancy more reliably than HT; despite only modest odds of spontaneous pregnancy in women with primary ovarian insufficiency, this is a critical consideration for those who deem pregnancy prevention a priority. Treatment for all women with primary ovarian insufficiency should continue until the average age of natural menopause is reached (age 50–51 years). Finally, considering the challenges that adolescents and young women may face in coping with the physical, reproductive, and social effects of primary ovarian insufficiency, comprehensive longitudinal management of this condition is essential.