p53 is the primary arbiter of the mammalian cell's response to stress, the governor of life and death. It is the nexus upon which signals converge from an array of sensors that detect damage to DNA or to the mitotic spindle or the cytoskeleton, hypoxia, cell detachment, growth factor deprivation, oncogene expression and other forms of stress. Depending on the type, intensity and duration of the signals, p53 in turn transactivates batteries of genes specifying cell cycle arrest, DNA repair, apoptosis, or other anti-neoplastic functions. At the same time, p53 represses anti-apoptotic and survival functions. The type, intensity and duration of signaling dictate the sequellae. While this response is combinatorial, the frequent perturbation of p53 function in a wide spectrum of cancers attests to its central role in the suppression of neoplasia. As our understanding of regulation by and of p53 has deepened, many possibilities have been suggested for re-establishing p53 or its effectors in tumor cells. This review will briefly summarize the role of p53 mutations in the etiology and treatment of breast cancer and then consider the wide array of strategies being developed to re-establish p53 function in tumor cells.