Pharmacogenomics research is yielding molecular diagnostic tools that can be used to optimize the selection of medications and their doses for individual patients. Given the narrow therapeutic index of most anticancer agents and the serious consequences of undertreatment, cancer chemotherapy is a compelling therapeutic area for translation of pharmacogenomics to the clinic. This review addresses how inherited (germline) and acquired (somatic) sources of genome variability can alter the toxicity or efficacy of cancer chemotherapy.