Abnormalities in the p53 tumor suppressor have been identified in over 60% of human cancers. The status of p53 within tumor cells has been proposed to be one of the major determinants of the response to anticancer therapies. In this review we examine the relationship between functional p53 and sensitivity, or resistance, to chemotherapy and radiotherapy. We also discuss the potential of current gene-therapy approaches to restore functional p53 to tumors as a means of modulating the effects of radiation and chemotherapy.