Here we review progress in our understanding of the complex role that p53 plays in controlling expression of cell-death regulatory pathways; how paradoxically, this may be important for cellular and organismal survival in response to homeostatic stress; the potential impact on the response to p53 activating therapies; and the ways that this might be exploited in cancer types for which maintaining wild-type p53 is beneficial. The gene discussed is TP53; the disease is cancer.