The p53 gene is the most commonly mutated gene known in human tumors; over half of human tumors contain inactivating mutations in p53. In the past decade, the role of p53 as apoptotic trigger has been well demonstrated both in vitro and in vivo. Many chemotherapeutic agents cause DNA damage and activate the p53 pathway to induce growth arrest and apoptosis. However, the p53 function is often inactivated or suppressed in human cancers. Thus, functional restoration of this pathway is an attractive therapeutic strategy. In recent years, a number of therapeutic approaches aiming at modulation of the p53 pathway have been developed and will be reviewed here. The focus will be on recent developments elucidating a transcription-independent mechanism of p53-mediated apoptosis and the therapeutic opportunities arising from this new mechanism.