Increasing numbers of children diagnosed with cancer will survive their primary malignancy. Within this growing population of long-term survivors, considerable effort has been put forth to identify treatment-related risks for adverse health-related outcomes, such as exposure to alkylating agents, anthracyclines, radiotherapy, and surgery. Patient sex has been identified as a risk factor for numerous long-term adverse outcomes, with female sex more commonly associated with higher risks. In this article, we review the literature, which generally supports associations between female sex and cognitive dysfunction after cranial irradiation, cardiovascular outcomes, obesity, radiation-associated differences in pubertal timing, development of primary hypothyroidism, breast cancer as a second malignant neoplasm and suggests an increased prevalence for the development of osteonecrosis among females. Results of this review support future investigations to further define sex as a risk factor for other common treatment-specific exposures and outcomes. Additionally, research should focus on understanding the underlying biologic and physiological basis of these sex-specific risks. Historically, evidence from both basic science and clinical research has been used to develop risk-stratified therapy, allowing reduction of toxic therapies to low-risk patients without compromising overall survival. With greater knowledge of sex-specific risks, the potential application of sex-specific therapy designed to avoid poor long-term adverse outcomes may become a viable strategy.