In the last four decades, advances in therapies for primary cancers have improved overall survival for childhood cancer. Currently, almost 80% of children will survive beyond 5 years from diagnosis of their primary malignancy. These improved outcomes have resulted in a growing population of childhood cancer survivors. Radiation therapy, while an essential component of primary treatment for many childhood malignancies, has been associated with risk of long-term adverse outcomes. The Childhood Cancer Survivor Study (CCSS), a retrospective cohort of over 14,000 survivors of childhood cancer diagnosed between 1970 and 1986, has been an important resource to quantify associations between radiation therapy and risk of long-term adverse health and quality of life outcomes. Radiation therapy has been associated with increased risk for late mortality, development of second neoplasms, obesity, and pulmonary, cardiac and thyroid dysfunction as well as an increased overall risk for chronic health conditions. Importantly, the CCSS has provided more precise estimates for a number of dose–response relationships, including those for radiation therapy and development of subsequent malignant neoplasms of the central nervous system, thyroid and breast. Ongoing study of childhood cancer survivors is needed to establish long-term risks and to evaluate the impact of newer techniques such as conformal radiation therapy or proton-beam therapy.