A common step in human cancer is the inactivation of the p53 tumor suppressor pathway. This occurs either by mutations in the coding region of the p53 gene itself, or equally commonly, by inactivation of pathways that are required for p53 to exert its cellular function. Dramatic new results from animal models and the widespread availability of p53 activating small molecules are yielding important new insights into the therapeutic and toxic effects of p53 and how these can be exploited for improving therapy of cancer and other diseases.