p53 acts as a central mediator of the cellular response to stressful stimuli. The growth-suppressive function of p53 is lost with mutation and this occurs commonly in human cancer. In addition to suppressing cancer development and progression, wild-type p53 further confers chemo-sensitivity and radio-sensitivity upon tumor cells. Accumulated evidence over the last two decades that wild-type p53 activity is required for the efficacy of radiation and chemotherapy has led to considerable interest in development of strategies to restore normal p53 function in tumors with defective p53-dependent signaling. A number of promising discoveries, based on the knowledge of structural and functional basis of p53 mutation, p53 degradation by MDM2 and p53 family proteins, provide a foundation for future drug design. Here we review the role of p53 in enhancing the sensitivity from radiation and chemotherapy and discuss current progress on therapies targeting p53.