The p53 protein is an inducible transcription factor with multiple anti-proliferative roles in response to genotoxic damage; unprogrammed proliferative stimuli; and deprivation of oxygen, nutrients, or ribonucleotides. Inactivation of the TP53 gene by mutation or deletion is the most common event in human cancer. Loss of p53 function compromises genetic homeostasis in cells exposed to mutagens and prevents normal cytotoxic responses to cancer therapies. Genetic and pharmacological approaches are being developed with the ultimate goal of restoring or controlling p53 functions in cancer patients. Genetic interventions aiming at expressing wild-type TP53 in cancer cells, either by retroviral or adenoviral transfer, have met limited clinical success. However, recently, the use of a defective adenovirus (ONYX-015) that selectively kills p53-incompetent cells has shown promising effects in pre-clinical and clinical studies. Pharmacological methods are under development to either stimulate wild-type p53 protein function or induce p53 mutant proteins to resume wild-type functions. These methods are based on small chemicals (CP-31388, PRIMA-1), peptides (CDB3), or single-chain Fv antibody fragments corresponding to defined p53 domains. In addition, detection of mutant TP53 may also serve as a marker for early cancer detection, prediction, and prognosis. In this review, we discuss the mechanisms underlying these approaches and their perspectives for cancer therapy.