Advances in the molecular analysis of pediatric tumors are providing unprecedented insight into the genetic and cellular changes that drive tumor development. The genomic changes that underlie tumor development include direct alterations to DNA sequence (mutations), chromosomal changes (deletions, insertions, translocations, and aneuploidy), and epigenetic changes. Through these alterations, tumor cells acquire the capacity to thwart normal proliferative controls. Six key hallmarks of cancer cells have been described by Hanahan and Weinberg and provide a useful framework for understanding cancer biology. Cancer cells must be able to sustain abnormal proliferation and circumvent the function of growth-suppressing genes, resist normal cell death programs, achieve replicative immortality, induce angiogenesis, and acquire the ability to metastasize. In addition to these intrinsic changes, the tumor microenvironment plays a critical role in supporting the growth and progression of cancer. Finally, a complex interaction of tumor cells with the cells of the immune system has profound impact on how cancer progresses. A deeper understanding of each of these aspects of cancer biology offers new opportunities and targets for therapeutic development.