The Children's Oncology Group (COG) recently celebrated the milestone of 50 years of pediatric clinical trials and collaborative research in oncology. Our group had its origins in the four legacy pediatric clinical trials groups: the Children's Cancer Group (CCG), the Pediatric Oncology Group (POG), the National Wilms' Tumor Study Group (NWTS), and the Intergroup Rhabdomyosarcoma Study Group (IRSG), which merged in 2000 to form the COG. Over the last 50 years, the survival rates for childhood cancer have risen from 10% to almost 80%. Outcome in acute lymphoblastic leukemia (ALL) has gone from a 6-month median survival to an 80% overall cure rate. We have modified therapies in most major diseases to induce remission with the fewest long-term sequelae. Here we look back on our advances but also look forward to the next 50 years, which will produce even more successful treatments that will be tailored to the specific patient, translating the tools of molecular genetics. Experience has clearly proven that everything we know about the diagnosis and management of childhood cancer is a result of research and the dramatic historical decrease in mortality from childhood cancer is directly related to cooperative group clinical research.