Despite the rarity of malignancies in children, their study has provided important insights into normal cellular growth regulation and into cancer development. Here we present a few vignettes in pediatric leukemia and sarcoma that highlight a number of trends in basic, translational, and clinical research. These include the application of new methodologies for oncogene discovery, new approaches to study oncogenes, the use of genetically engineered models to identify tumor cell-of-origins, and the use of targeted therapeutics against pathways not thought to be mutant in tumor cells. Through the use of such methodologies, an improved understanding of pediatric malignancy is emerging, and is being applied to the care of children with cancer.