Inactivation of p53-mediated signaling plays a major role in both the genesis and therapy resistance of human cancer. Nearly all tumors contain mutations in p53 itself or have perturbations in the p53 pathway. Since there is clear evidence that many tumor cells are more likely to die in response to wild-type p53 activation or restoration than are their normal counterparts, there has been considerable interest in the development of small molecules that target p53 for therapeutic gain. These include compounds that either revert mutant p53 back to its wild-type conformation or compounds which interfere with the binding to, or the ubiquitylation of, p53 by MDM2. In both cases, however, the efficacy of the strategy depends on the presence of either mutant or wild-type p53 respectively thereby limiting their application to specific tumor settings. As a result, recent strategies have turned to the p53 family member, p73, which like p53 is a potent inducer of death, but in contrast is rarely lost or mutated in tumors. We discuss here all these different strategies and in particular focus on the discovery of an apoptotic peptide which targets not just p73, but potentially all p53 family members to cause tumor cell death.