Nuclear receptors for retinoids (RARs) and vitamin D (VDR), and for some other ligands (TRs, PPARs and LXRs), maybe critical in the development and homeostasis of mammalian epidermis. It is believed that these receptors form heterodimers with retinoid X receptors (RXRs) to act as transcriptional regulators. However, most genetic approaches aimed at establishing their physiological functions in the skin have been inconclusive owing either to pleiotropic effects and redundancies between receptor isotypes in gene knockouts, or to equivocal interpretation of dominant-negative mutant studies in transgenic mice. Moreover, knockout of RXRalpha, the main skin RXR isotype, is lethal in utero before skin formation. Here we have resolved these problems by developing an efficient technique to create spatiotemporally controlled somatic mutations in the mouse. We used tamoxifen-inducible Cre-ER(T) recombinases to ablate RXRalpha selectively in adult mouse keratinocytes. We show that RXRalpha has key roles in hair cycling, probably through RXR/VDR heterodimers, and in epidermal keratinocyte proliferation and differentiation.