The molecular structure of the biological active form of vitamin D, 1 alpha,25-dihydroxyvitamin D3 (VD), and the vitamin A derivatives all-trans and 9-cis retinoic acid (RA) are not related. The nuclear receptors for VD (VDR) and retinoids (RAR and RXR), however, are members of the same superfamily of ligand-activated transcription factors. We observed stable VDR-RXR and VDR-RAR heterodimers in solution and their transcriptional activity on different types of response elements. Both heterodimeric complexes are activated by VD, but, depending on the relative expression of the nuclear receptors, retinoids can have either co-stimulating or repressing effects. This demonstrates that VD and retinoid signaling are linked at the level of gene regulation and may explain the similar effects of both hormones on cell proliferation and differentiation. This concept may be applied for treating skin diseases, with the hope that a synergism will be observed, allowing better responses with lower doses of each compound. Preliminary observations suggest that psoriasis, cutaneous T-cell lymphomas, and actinic keratoses might be potential targets for VD-retinoid associations.