Background: It has been established in several models that the p63 gene has an important role in the development of the epidermis and its derivatives. In Xenopus, only the ΔNp63 isoform of this gene has been cloned and its role during epidermal development remains unknown. Results: In this work, we showed that ΔNp63 is expressed in the nonneural ectoderm since the gastrula stage and that it is regulated by the bone morphogenetic protein 4 (BMP4) signaling pathway. Our in vivo and in vitro experiments demonstrated that ΔNp63 is required in the earliest inductive steps of epidermal development. The overexpression of ΔNp63 caused an increase in epidermal markers with a suppression of neural induction while the blocking of ΔNp63 led to the opposite results. Finally, we found that ΔNp63 acts as an anti-apoptotic gene, regulating the transcription of some apoptotic and anti-apoptotic factors. Conclusion: The results suggest that ΔNp63 is an essential gene in early epidermal specification under the control of BMP4. Developmental Dynamics 241:257–269, 2012. © 2011 Wiley Periodicals, Inc.