Loss of p53 function compromises genetic homeostasis in cells exhibiting deregulated DNA replication and/or DNA damage, 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. Progress has recently been made in the clinical use of replication-deficient virus carrying wt-TP53 (Ad5CMV-p53) and/or cancer-selective oncolytic adenoviruses (ONYX-015). These strategies demonstrated clinical activity as monotherapy and were synergistic with traditional chemotherapy agents in the treatment of some types of cancer. In addition, 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. Here, we discuss the mechanisms underlying these approaches and their perspectives for cancer therapy.