Homology between p63 and p53 has suggested that these proteins might function similarly. However, the majority of data from human tumors have not supported a similar role for p63 in tumor suppression. To investigate this issue, we studied spontaneous tumorigenesis in p63+/− mice in both WT and p53-compromised backgrounds. We found that p63+/− mice were not tumor prone and mice heterozygous for both p63 and p53 had fewer tumors than p53+/− mice. The rare tumors that developed in mice with compromised p63 were also distinct from those of p53+/− mice. Furthermore, p63+/− mice were not prone to chemically induced tumorigenesis, and p63 expression was maintained in carcinomas. These findings demonstrate that, in agreement with data from human tumors, p63 plays a markedly different biological role in cancer than p53.