The discovery of two new p53 homologs, p73 and p63, has defined a family of transcription factors heavily involved in the control of growth suppression, apoptosis, differentiation and development. While p53-deficient mice undergo spontaneous tumors, p73 and p63 knockout mice exhibit severe developmental defects. We demonstrate here that p73 gene is an in vivo transcriptional target of the muscle regulatory factors MyoD, myogenin, Myf5 and Myf6. Ectopic expression of the transcriptional repressor δEF1/ZEB/zfhx1a counteracts MyoD/Myf5-or MyoD/Myf6-mediated transcriptional activation of p73. A distinct pattern of in vivo recruitment of muscle regulatory factors and δEF1 on p73 regulatory regions was found between proliferating and differentiating muscle cells. We also found that δEF1 plays a role in the transcriptional regulation of p53 family members during keratinocytic differentiation. Mouse embryo fibroblasts derived from δEF1-deficient mice exhibit unbalanced expression of ΔNp63, TAp73 and ΔNp73 but not of TAp63 and p53. The analysis of tissues derived from δEF1+/− mice exhibit a selective enrichment of ΔNp63 in skin.