The past decade has brought together substantial advances in human genome analysis and a maturation of understanding of tumor biology. Although there is much progress still to be made, there are now several prominent examples in which tumor-associated somatic mutations have been used to identify cellular signaling pathways in tumors. This in turn has led to the development of targeted therapies, with somatic mutations serving as genomic predictors of tumor response and providing new leads for drug development. There is also a realization that germline DNA variants can help optimize cancer drug dosing and predict the susceptibility of patients to the adverse side effects of these drugs-knowledge that ultimately can be used to improve the benefit:risk ratio of cancer treatment for individual patients.