Despite its demonstrable effective therapeutic ratio in children, the use of radiation therapy in children and young adults has been limited by concerns for acute and late effects. These concerns are variably appropriate and inappropriately leverage on individual cases depending on the practitioner’s experiential and literature-based knowledge of the patient-specific factors in play. The inappropriate estimation of the morbidity of the application of local therapy may have severe consequences and thus lead to therapy omission and premature treatment failure or even death. As a result, a thorough knowledge of the implications of radiation therapy should be carefully considered and be guided by a combination of multidisciplinary experiences and strong, objective literature review. This chapter is intended to serve as a foundation for further clinical and academic investigation and application to clinical decision-making and thoughtful scholarship so that the therapeutic ratio is well defined in so much as is possible, and uncertainties are acknowledged in day-to-day practice.