Over the last few decades, long-term survival rates of children diagnosed with the two most common forms of childhood cancer, acute lymphoblastic leukemia (ALL) and brain tumors have improved substantially. Neurodevelopmental and psychosocial sequelae resulting from these diseases and their treatment have a direct impact on the developing brain and on the quality of life of these children and their families. The focus of this article is on optimizing neuropsychological and adaptive outcomes for children who have been successfully treated for these cancers and whose prospects for long-term survival are increasingly encouraging. We present a model for understanding systemic interactions among the multiple factors that influence the child's development over time and take into account contextual variables. Strategies for optimizing cognitive and psychosocial outcomes or ameliorating late effects need to consider treatment histories, specific stages of development, the contextual demands/developmental challenges associated with each, and the resources (internal and external to the child) available to meet these challenges. The challenges faced by survivors at the early childhood, middle childhood, adolescent, and emerging adulthood stages are discussed. We review different types of interventions and discuss how these can contribute to optimal functioning in survivors of childhood ALL and brain tumors.