ABSTRACT The Childhood Cancer Survivor Study (CCSS) is a multi-institutional, multi-disciplinary collaborative research resource established to systematically evaluate long-term outcomes among children diagnosed with cancer who survived five or more years from diagnosis. With the successful recruitment and longitudinal follow-up of the cohort that includes survivors diagnosed and treated over three decades (1970-1999), the CCSS is the world's largest established open resource for survivorship research with 38,036 eligible survivors available for investigation of late mortality, and 25,665 participants who have contributed health-related and quality of life outcomes. The resource includes comprehensive annotation of treatment exposures, ongoing longitudinal follow-up and an established biorepository from which genotype (SNP array) and DNA sequencing of 8,380 survivors are available to investigators for identification of genetic susceptibility for disease- and treatment- related late effects. Extensive use by the research community has resulted in: 381 published or in press manuscripts now cited over 26,500 times; 347 presented abstracts; 59 investigator-initiated grants funded, totaling $67 million in funding; utilization by a diverse group of 1,225 investigators including 91 early career trainees; conduct of 11 randomized trials; increased knowledge to inform exposure-based clinical care guidelines; and a highly successful model for multiple national and international collaborative initiatives of pediatric cancer survivorship research. During the next five years, activities will ensure the functioning of CCSS as a strong and productive resource by maintaining, enhancing and promoting its use. We will expand the collection of data to evaluate physiologic and neurocognitive function with aging, characterize accelerated aging, and investigate underlying pathophysiology of aging of survivors as they enter into their fourth, fifth and sixth decades of life. To develop a population resource for intervention trials targeting age-related outcomes, in-home functional performance assessment and specimen collection will be performed in a sub-cohort of 1000 survivors. Further, we will enhance the CCSS resource by facilitating the conduct of health services research through collection of data to evaluate patient, provider, and health care system factors and their associations with access, quality, and cost of care. To maximize the research community's access and use of the CCSS resource, we will leverage a cloud-based data sharing platform and develop a data analysis ecosystem with tools for data access, visualization and analysis of genetic, treatment and phenotypic/outcome data. In the future, assessment of late outcomes of novel therapies (immunotherapy, targeted/biologic, proton beam radiation) will be essential. Therefore, with NCI oversight, CCSS will formulate a comprehensive plan for future expansion. These initiatives will enhance and promote CCSS to...