The tumor suppressor p53 is a linchpin in the regulation of appropriate cellular responses to various stress conditions. Inactivation of the functions of this critical participant can have diabolical consequences, in particular the development of malignant diseases. Elicitation of appropriate p53 functions is an attractive strategy for combating cancer. Triggering p53 responses, reconstituting p53 activities through gene therapy, coercing mutant p53 to perform normal functions, manipulating p53 regulators, and activating p53 effectors are all approaches that are currently being developed. Here, we will overview 'p53-based' strategies for fighting cancer, both those under clinical trial and recent innovative concepts.