Small molecules that activate the transcriptional function of wild type p53 have proved active as anti-cancer drugs in preclinical models and are now entering clinical trial. The complexity of the upstream p53 signaling pathway offers many targets for the devel-opment of such activators and the action of Mdm2 inhibitors, kinase inhibitors, sirtuin inhibitors and low doses of actinomycin D will be described among other examples.