The role of p53 as a central mediator of the DNA damage and other cellular stress responses is well established. The ultimate growth-suppressive function of p53 in part explains its ability to confer chemosensitivity and radiosensitivity upon tumor cells. Recent work in the field has added complexity to our understanding, in terms of identifying novel regulators of p53 stability and function, elucidation of the importance of the p53 family towards p53 function, a growing list of transcriptional targets as well as transcription-independent apoptotic effects and mechanisms, tissue specificity of the p53 response, a molecular understanding of p53-dependent therapeutic sensitization, and efforts towards molecular targeting of the p53 pathway. p53 remains an attractive target for drug development in cancer because its alteration provides a fundamental difference between normal and cancer cells. Strategies are emerging for the identification of mutant p53-specific therapies, therapies targeted at mutant p53-expressing tumors, as well as therapies that target various aspects of the p53 life cycle to enhance chemosensitization. The tools of molecular imaging are beginning to accelerate the pace of discovery and preclinical testing of p53 in animal models. The future holds promise for specific, individualized targeting of mutant or wild-type p53, or its transcriptional targets, in combination therapies with other cancer-specific drugs, to maximize tumor cell killing while protecting normal cells from toxic side effects.