An inducible epidermal-specific knockout system, which utilizes epidermal-specific expression of a Cre recombinase that is fused with a truncated progesterone receptor (PR1), was developed. The CrePR1 fusion protein is bound and activated by progesterone antagonists, such as RU486 or its analogue ZK98.734. When the CrePR1 transgenic mice were crossed with a floxed target mouse line to generate bigenic mice, an epidermal-specific knockout of the target gene was induced by topical application of a progesterone antagonist. A keratin K14 vector was used to target CrePR1 expression to the epidermis (K14.CrePR1) To confirm that K14.CrePR1 could mediate the inducible excision of a loxP flanked gene, K14.CrePR1 and CAG-CAT-Z Cre reporter mice were mated. Results showed that the β-gal expression in the bigenic skin containing the CAG-CAT-Z transgene was primarily in the differentiated layers of the epidermis, with focal expression in the basal cells, and no expression in hair follicles. These results document the differential expression of the CAG and ROSA26 promoters in the epidermis and hair follicles.