Initially described as an oncogene, at the end of the 1980s, the wild-type p53 gene (TP53) was later shown to be capable of suppressing the proliferation of transformed cells. In the following years, an increasing number of studies demonstrated that intact p53 function is essential for the maintenance of the non-tumorigenic phenotype of cells. Indeed, functional inactivation of the p53 protein is one of the most common alterations observed in human cancers. More recently, it has been shown that inactivation of the TP53 tumor suppressor gene may lead to radioresistant and chemoresistant tumors, possibly by the induction of apoptosis-resistant phenotypes. Finally, a large number of in vitro and in vivo transduction experiments have demonstrated that exogenous TP53 overexpression can suppress the transformed phenotype of many cell types by inducing growth arrest, apoptosis or cell differentiation. All of these findings have rendered p53 a potentially helpful target for the therapy of many types of human cancers. In this review we shall discuss the different approaches to p53-related cancer therapy that have been proposed on the basis of this large number of experimental studies, and we shall try to dissect the biological questions that are still open and need to be clarified to improve p53-based therapy.