Retinoic acid (RA) and thyroid hormone (T3) are important regulators of epidermal growth, differentiation and homeostasis. Retinoic acid and its derivatives are used extensively in the treatment of many disorders of epidermis and cutaneous appendages. RA and T3 directly control the transcription of differentiation-specific genes, including those for keratins, through the specific nuclear receptors, RAR and T3R, which react with corresponding response elements. We have previously identified the response element in the K14 gene, K14RARE/TRE, and found that it consists of a cluster of 5 half-sites with variable spacing and orientation. To determine whether this specific structure is common in other keratin genes, we have mapped and analyzed the RARE/TRE elements in three additional epidermal keratin genes: K5, K6 and K17. We used three different approaches to identify these elements: co-transfection of promoter deletion constructs, gel-shift assays and site-specific mutagenesis. In all three promoters we localized the RARE/TRE elements relatively close to the TATA box. All three RARE/TRE elements consist of clusters of three to six half-sites with variable spacing and orientation, as does the previously identified K14RARE/TRE. This means that the clustered structure of the RARE/TREs is a common characteristic for keratin genes. Interestingly, RARE and TRE in the K5 promoter are adjacent to each other whereas in K17 they overlap. In summary, this study identifies and characterizes a new group of the native negative nuclear receptors response elements that operate in the epidermis.