Patients with gynecologic, gastrointestinal, or genitourinary malignancy are at elevated risk of developing premature ovarian insufficiency from the multimodality therapies used to treat their cancers. Premature ovarian insufficiency can result in long-term decrements to all-cause mortality, bone density, cardiovascular health, sexual health, cognitive health, and body mass. Hormone replacement therapy has been demonstrated to reverse these long-term sequalae with the goal of restoring estrogen concentrations to physiological levels. Here, we discuss a practical approach for initiation of hormone replacement therapy as well as challenges to consider.