Previous work has shown that a dominant-negative RAR (dnRAR), expressed under the K14 promoter, causes severe epidermal defects. Similar defects are, however, not seen in RAR double null mutant mice, which lack the entire complement of RARs expressed in the epidermis. To investigate the mechanism of action of such dominant-negative receptors, dnRAR or a DNA-binding deficient variant, dnRAR^DBD, were targeted to the basal epidermis. Expression of either receptor type led to similar epidermal phenotypes suggesting that both RAR mutants acted through a common mechanism. The epidermal phenotype was reminiscent of defects seen in p63-/- mice. Consistent with this, reduced p63 expression was observed in transgenic offspring expressing either RAR mutant, suggesting that downregulation of p63 might underlie the effects of these receptors on epidermal development. By contrast, expression of p63 in the epidermis of RAR-/- offspring was unaffected, indicating that RARs were not essential for p63 expression. These findings suggest that dnRARs may impact on epidermal development through a non-canonical pathway(s) which is independent of receptor-DNA interaction.