The p53 tumor suppressor protein plays a central role in mediating the cellular response to a variety of stresses. Activation of p53 signaling will trigger cell cycle arrest or apoptosis in normal cells, depending on such factors as cell type and genetic context. The ability of a cell to circumvent either of these p53-directed outcomes leads to inappropriate proliferation, thereby contributing to the development of cancer. As such, tumors frequently escape the apoptotic pathway in response to cell stress. DNA-damaging agents, however, achieve significant tumor cytotoxicity in spite of this hallmark characteristic. Tumors treated with DNA-damaging drugs often undergo alternate forms of cell death, such as senescence or mitotic catastrophe, in addition to apoptosis that may ultimately lead to regression. Although not a predictor of chemotherapy response in patients per se, p53 status in tumor-derived cells is frequently a determinant of the death pathway promoted by these agents. The cytotoxic effects of DNA-damaging agents can be readily appreciated using such tools as cell cycle analysis, phopsho-H3(Ser10) immunoblotting, and annexin V detection.