The tumor suppressor p53 normally acts to appropriately coordinate cellular responses to stress stimuli. When p53 activity is disabled, the onset of malignancy is a potential consequence. Engendering wild type p53 activities in cells that lack these functions is an approach that is currently being explored for cancer therapy. Eliciting elevated levels of active p53, imparting p53 activities through gene therapy, compelling mutant p53 to perform normal functions, manipulating p53 regulators, and activating p53 effectors are all approaches that are currently being developed. In this review we will provide a synopsis of the most promising 'p53-based' strategies for fighting cancer, both those under clinical trial and recent innovative concepts.