Keratin 6 (K6) is an intermediate filament protein found in hair follicles and in several internal stratified epithelia. This keratin has been the focus of special attention because it is also strongly induced in epidermal interfollicular keratinocytes in hyperproliferative situations and in certain conditions leading to abnormal differentiation. To localize and identify the sequences controlling this complex expression pattern, and because of their potential use in transgenic mouse models and gene therapy strategies for epidermal hyperproliferative disorders, we have thoroughly analyzed a 9 kbp region of this gene previously shown to direct proper tissue-specific and inducible expression in transgenic mice. To reproduce the K6 constitutive expression pattern, cooperation is necessary between elements located in at least two different regions, one distal between -9 and -4 kbp and one proximal between -830 and -125 bp with respect to the CAP site. The ability to induce expression under hyperproliferative conditions resides in the 2.4 kbp fragment preceding the transcription start site. When this DNA fragment was analyzed in more detail, we found that all subfragments tested contained regulatory elements necessary for inducible expression. Thus, a complex organization of K6 regulatory elements emerges, as both the constitutive and the inducible expressions of this gene are under the control of multiple elements dispersed throughout relatively large 5′ flanking DNA fragments. These findings will allow the expression of cloned genes in transgenic mouse skin in response to pathological or applied hyperproliferative stimuli, avoiding the effects of their constitutive expression in other epithelia.