Since the introduction of chemotherapy for the treatment of childhood leukemia more than sixty years ago, the, prognosis for children with cancer has improved dramatically. The 5-year survival rate for childhood cancers, many of which were uniformly fatal in the pre-chemotherapy era, is now approaching.80%. Despite these advances, several childhood cancers still have unacceptably low cure rates, and even when treatment is successful, the acute and long-term morbidity of current therapy can be substantial. The Children's Oncology Group (COG), the world's largest organization devoted exclusively to childhood and adolescent cancer research, was founded 12 years ago. The COG's multidisciplinary research team, comprised of more than 8,000 members, conducts research at more than 200 leading children's hospitals, universities, and cancer centers. This proposal is for COG, as part of NCI's new National Clinical Trials Network, to continue its collaborative research work that supports the mission of improving the outcome for all children with cancer. The COG will design and conduct clinical-translational studies for children with cancer that builds on an increasing understanding of the molecular basis for pediatric malignancies and has the highest potential to improve the outcome. Using innovative clinical trial designs suitable for the study of rare diseases, we will study novel therapeutic approaches that range from targeted, small molecules to cellular therapies. As more than 90% of children diagnosed with cancer in the US are treated at COG member institutions, the COG has the ability to offer to children with cancer and their families to participation in research that allows for collection and annotation of biospecimens from all children with cancer, providing the foundation for discovery and accelerating the most promising research efforts conducted in laboratories around the world. The COG research portfolio importantly also includes research trials focused on improving the quality of life children with cancer and survivors. The proposal is for support of the COG Group Operations Center, clinician-scientists who develop and conduct research, and for member sites to participate through enrollment of eligible subjects.