Survivors of childhood cancer represent a rapidly growing population of patients, some of whom experience temporary or permanent premature ovarian failure (POF) as a consequence of their disease or treatment. Although the risks and benefits of exogenous hormones have been extensively explored in menopausal women 50 years of age and older, there is scant data on the long-term safety of exogenous hormones in childhood cancer survivors. Although there are certainly benefits that can be achieved through hormone replacement for this unique population, many of these patients also have very long hormone exposure times and a markedly increased baseline risk for second malignancies, including breast cancer. Given the significant potential risks, hormone replacement should not be reflexively instituted in childhood cancer survivors with POF. It should only be considered following a thorough, balanced discussion of the risks and benefits of hormone replacement with each patient.