During the past 30 years, changes in the treatment of children and adolescents with cancer have led to substantial improvements in survival. Although treatment-related factors have been shown to impact subsequent health status and quality of life, there is limited information on survivors who are now two or more decades after treatment. The Childhood Cancer Survivor Study (CCSS) was established as a resource for investigating the long-term outcomes of a cohort of 5-year survivors of childhood and adolescent cancer, diagnosed between 1970-1986. The CCSS cohort has more than 14,000 active participants, including survivors of leukemia, brain tumors, Hodgkin disease, non-Hodgkin lymphoma, Wilms tumor, neuroblastoma, soft-tissue sarcoma, and bone tumors. Study participants, extensively characterized by their cancer therapy, have provided self-reported sociodemographic- and health-related information. Although the survivor population has been found to be at significantly increased risk of several adverse outcomes, such as late mortality, second cancers, pulmonary complications, pregnancy loss, low birth weight of offspring, and decreased education, the overall proportion of survivors affected is relatively small. Subgroups at high risk of adverse outcomes, defined by treatment-related, demographic, or medical factors, can be identified. The ongoing evaluation of large and diverse cohorts of cancer survivors will aid in further identifying individuals who should be the target of innovative intervention strategies.