The in vivo effects of steroid hormones are mediated by specific receptors that belong to a large super-family of ligand-dependent transcription factors. Glucocorticoids, widely used in topical and systemic therapy, affect epidermal cell differentiation and replication, proliferation of dermal fibroblasts and synthesis of matrix proteins. Estrogens increase mitotic rate in epidermis, reduce activity of sebaceous glands, slow hair growth and stimulate synthesis of collagen. We have analyzed regulation of keratin genes, markers of epidermal differentiation, by receptors for glucocorticoid and estrogen hormones, and by COUP-TFII, an orphan receptor, which is a member of the same family. We have found that dexamethasone suppresses expression of keratins K5, K6, K10, K13, K14, K16, K17 and K19 while K8 and K18 are not regulated. The thyroid hormone receptor blocks dexamethasone-mediated suppression, which implies a regulatory nexus among steroid hormones, thyroid hormone and retinoids, possibly involving shared DNA recognition elements. Similarly, estrogen receptor suppresses all keratin genes tested, except hyperproliferation-specific pair K6 and K16. In contrast, COUP-TFII induces expression of K5, K6, K10, K14, K16, K17 and K19 while suppressing K8 and K18. These results, combined with our previous findings of regulation by thyroid/retinoid receptors, suggest that a combination of hormonal effects leads to the particular phenotype of specific keratinocytes.