The transcription factor p63 is essential for the formation of the epidermis and other stratifying epithelia. This is clearly demonstrated by the severe abnormality of p63-deficient mice and by the development of certain types of ectodermal dysplasias in humans as a result of p63 mutations. Investigation of the in vivo functions of p63 is complicated by the occurrence of 10 different splicing isoforms and by its interaction with the other family members, p53 and p73. In vitro and in vivo models have been used to unravel the functions of p63 and its different isoforms, but the results or their interpretation are often contradictory. This review focuses on what mammalian in vivo models and patient studies have taught us in the last 10 years.