p63, an ancestral transcription factor of the p53 family, has three C-terminal isoforms whose relative in vivo functions are elusive. The p63 gene is essential for skin and limb development, as vividly shown by two independent global knockout mouse models. Both strains, although constructed differently, have identical and severe phenotypes, characterized by absent epidermis and hindlimbs and only rudimentary forelimbs at birth. Here we show that mice from one model, Brdm2, express normal levels of truncated p63 proteins that contain the DNA binding and oligomerization domain but lack the long carboxy-terminal SAM (sterile α-motif) and post-SAM domains that are specific for the α and β isoforms. As such, transcriptionally active p63 proteins from Brdm2 mice resemble the naturally occurring p63γ isoforms, which of all the p63 isoforms most closely resemble p53. Thus, Brdm2 mice are p63α/β isoform-specific knockout mice, gaining unexpected new importance. Our studies identify that p63α/β but not p63γ are absolutely required for proper skin and limb development.