Since its discovery 25 years ago, the tumor suppressor p53 has been a subject of intense study, yielding in excess of 30 000 research articles. The high interest in this molecule is largely due to the fact that p53 is the most frequently altered protein in human cancer. Approximately 50% of all human malignancies harbor mutations or deletions in the TP53 gene that disable the tumor suppressor function of the encoded protein. 1, 2 This high rate of genetic alterations underscores the important cellular function of p53. The tumor suppressor controls a signal transduction pathway evolved to protect multicellular organisms from cancer development that could be initiated by diverse stresses including DNA damage. p53 is a potent transcription factor capable of activating multiple target genes, leading to cell cycle arrest, apoptosis, or senescence. 3, 4 While p53 plays a protective role in normal somatic tissues by limiting the propagation of damaged cells, its powerful growth suppressive and proapoptotic activity could be turned into a powerful weapon against cancer cells that have retained the functionality of the p53 pathway. Fortunately, half of all human tumors express wild-type protein that is capable of activating p53 target genes. However, aberrations in p53 regulation and signaling mechanisms could attenuate the tumor suppressor function of p53. One such aberration involves the product of the murine double minute-2 gene (MDM2), a negative regulator of p53 activity and stability. 5r7 MDM2 is overexpressed in many human tumors and effectively impairs the function of the p53 pathway. 8 Therefore, restoration of p53 function by antagonizing MDM2 has been proposed as a novel approach for treating cancer, and studies using macromolecular tools have shown its validity in vitro. 9r11 Several classes of low molecular weight inhibitors of the p53rMDM2 interaction have been reported that can disrupt the binding between the two proteins. Recently, the first potent and selective small-molecule antagonists of MDM2 have been developed. 12 These druglike molecules, termed nutlins, have shown the ability to activate the p53 pathway in vitro and in vivo and provided a proof of concept for the therapeutic utility of MDM2 antagonists in tumors with wild-type p53. This Perspective examines the latest developments in the search for pharmacological activators of wild-type p53 with emphasis on agents that antagonize the p53rMDM2 interaction.