The use of molecular approaches has become part of the standard of care in the management of pediatric cancer patients. Molecular approaches are now included in the initial diagnosis, definition of prognostically distinct patient subgroups, selection of patients for specific therapies, prediction of risk for toxicities to therapy, and monitoring of patients receiving both conventional and novel targeted therapies. This clinical application of molecular medicine has been based on a growing molecular understanding of cancer biology. Studies of pediatric cancers have contributed to this understanding in many ways. We present a model for understanding cancer biology, using specific examples taken from pediatric oncology, and then discuss the application of molecular techniques to the clinical management of pediatric cancer patients.