As therapeutic and supportive care interventions become increasingly effective, growing numbers of childhood and adolescent cancer survivors face a myriad of physical and psychological sequelae secondary to their disease and treatment. Mental health issues, in particular, present a significant problem in this unique patient population, with depression affecting a sizable number of childhood and adolescent cancer survivors. Multiple key determinants impact a survivor's risk of developing depression, with variables traversing across biologic, individual, family, community, and global levels, as well as spanning throughout the life course of human development from the preconception and prenatal periods to adulthood. A multi-level life course conceptual model offers a valuable framework to identify and organize the diverse variables that modulate the risk of developing depression in survivors of childhood and adolescent cancer. This review describes the first multi-level life course perspective applied to development of depression in childhood and adolescent cancer survivors. This conceptual framework may be used to guide the investigation of mental health interventions for SCACs to ensure that key determinants of depression occurrence are adequately addressed across various levels and throughout the life trajectory.