Obesity at diagnosis is a negative prognostic indicator for several pediatric cancers including acute leukemia and bone tumors. Incidence of obesity in children has increased three-fold over the past 2 decades, and causes for this include poor diet, excessive caloric intake, and lack of physical activity, which are collectively referred to as energy balance-related behaviors. Few energy balance interventions have been implemented in pediatric cancer patients during treatment, and here we will probe the rationale for pursuing such studies. The need to modify composition of calories consumed and to identify specific beneficial exercise regimens will be discussed, relative to weight reduction or management.