Because many adverse effects of treatment for childhood cancer may not become clinically apparent until the survivor attains maturity or older ages, continued follow-up across the lifespan, from childhood through adulthood, is essential. With more than 420,000 childhood cancer survivors in the U.S., there is a critical need to accurately characterize the development and manifestation of very late cancer-related sequel. In 2007, St. Jude Children's Research Hospital initiated a unique clinical (i.e., medically evaluated) cohort with the primary aim of establishing lifelong evaluation of health-related and quality of life outcomes in aging adult survivors of pediatric cancer. Eligibility for participatio in the St. Jude Lifetime Cohort (SJLIFE) is survival > 10 years from diagnosis, and attained age of > 18 years. As of January, 2014, 3026 survivors (90 percent of those contacted and 80 percent of those eligible) have successfully completed one or more evaluations (typically involving a 3-4 day outpatient visit) providing a rich repository of biospecimens and outcomes data that has been used to more accurately characterize the prevalence of adverse biomedical and psychosocial outcomes, to identify demographic, genetic, treatment and psychosocial/behavioral-related predictors of negative health outcome, to inform ongoing health surveillance recommendations, and to guide health preserving interventions. The SJLIFE cohort has yielded important findings including determination of a more accurate prevalence of cancer treatment-related organ dysfunction among adults treated for cancer during childhood, investigation of innovative methods of health surveillance, and identification of novel and unexpected late health outcomes. However, the current sample size of the SJLIFE cohort, its restriction to adult participants (i.e., those 18+ years), and methods utilizing risk-directed screening imposes limits on the potential for significant new discovery. Thus, to enhance the SJLIFE cohort and its ability to advance our understanding about how the diagnosis of cancer during childhood and its associated therapeutic exposures impact long-term health, we propose to: (1) expand eligibility of the SJLIFE cohort to include a clinically well-characterized cohort o five- year survivors, (2) undertake uniform medical assessments in all cohort participants, (3) develop and test innovative methodologies to maintain the SJLIFE cohort, and (4) establish a resource for future innovative intervention-based research. Over the five-years of the grant, the SJLIFE cohort will be expanded to include approximately 9800 five-year survivors (i.e., evaluable for late mortality), of whom 7825 are projected to be alive and will agree to actively participate in SJLIFE (i.e., available for longitudinal assessment of morbidity and quality of life outcomes). The SJLIFE cohort will be unique in its ability to provide new insights into the risks and pathophysiology of morbidity associated with cancer and its therapy, which is critical to the design of contemporary treatment protocols and public health initiatives to facilitate survivor access to preventive and remedial services.