The Children's Oncology Group (COG) is a new multidisciplinary clinical trials group resulting from the unification of the four pediatric cooperative groups. It is the largest childhood cancer research organization in the world and encompasses approximately 238 pediatric cancer programs as clinical trial sites throughout all of North America, Australia, and several institutions in Europe. It is exclusively well poised to translate basic biology studies into clinical investigations and to develop translational approaches through human proof of principle, toxicity assessment, identification of efficacy, and ultimately, incorporation into established treatments to improve outcome and/or decrease toxicity. COG represents the legacy of four groups, the oldest of which existed for nearly 50 years. Currently, 48,259 patients accrued to clinical trials are in active follow-up; over 2,500,000 person years of life have been saved. Although childhood cancer mortality has decreased by 50% in the last two decades and by 25% inthe past decade, nearly 2,500 children and adolescents die from cancer annually inthe U.S. alone. The majority of these deaths can be attributed to specific pediatric cancers for which new therapeutic approaches must be devised. Improvement in the cure rates for these high-risk cancers is more likely to emerge as a result of the identification of biologic features which predict resistance and, more importantly, by the identification of new anti-cancer agents with novel mechanisms of action, whose efficacy might be predicted on the basis of specific unique molecular abnormalities detected in cancer cells. COG is also uniquely able to establish for the first time a North America-wide population-based registry of childhood cancer to investigate, utilizing case control studies, potential epidemiologic associations, including genetic alterations and ultimately interactions of genes with the environment. COG, through a series of hypothesis-driven research studies, seeks to maximize cure rates for children with cancer; to achieve an expanded understanding of tumor and host biology; to elucidate new therapeutic strategies and to build on the concept of risk-adjusted therapy; and to reduce treatment-related toxicity and morbidity, thereby optimize quality of life and survival.The proposed research is aimed at reducing deaths from childhood cancer by 20% and increasing 5-year disease-free survival (cure) rates to >85% during the study period.