In the two decades since its original discovery, p53 has found a singularly prominent place in our understanding of human cancer. Although the biochemistry of p53 has been worked out in some detail, our knowledge of the biologic consequences of p53 dysfunction is still quite rudimentary. Over the next several years, it will be important to determine how best to harness the complex properties of p53's ability to induce cellular growth arrest and cell death to generate novel, effective approaches to cancer therapy. Furthermore, a clearer appreciation of the direct interaction of epigenetic factors with p53 will lead to development of strategies to inhibit tumour initiation and progression. The next decade promises to offer exciting opportunities to apply our vast knowledge of this intriguing tumor suppressor to clinical advantage.