The phenotypes of the p63 mutant mice are complex and diverse. The p63-/- mice develop severe defects in morphogenesis of ectodermal appendages, and p63+/- mice are tumor prone. Transcriptional targets of p63 with functions in both of these biological processes likely exist. Here, we identified one such direct transcriptional target of p63, brachyury, a gene with diverse roles in limb development and tumorigenesis. We found that brachyury is not expressed in developing p63-/- mouse embryos, and that in osteosarcomas, ΔNp63 and brachyury are expressed at high levels. Knock down of ΔNp63 in tumor cells resulted in a concomitant diminution of brachyury, cell proliferation, migration and invasion. These data provide evidence that suppression of ΔNp63 in tumors may lead to tumor regression through loss of cell proliferative and metastatic potential.