Somatic gene therapy remains a promising therapeutic approach for both inherited and acquired disorders. Among the tissues amenable to gene therapy, the skin, and particularly the epidermal cells, present several features advantageous for genetic manipulation and monitoring of therapeutic effects. Candidate diseases for cutaneous gene therapy not only involve skin defects but also systemic abnormalities. The robust basic and pre-clinical data gathered during the last few years have allowed the imminent launching of keratinocyte-based gene therapy with applications to patients.