Genetic correction of monogenic human skin disorders represents a potentially effective molecular therapy for severe diseases in which current therapy is only palliative. The stratified epithelium of the epidermis represents the tissue location with the largest number of genetic skin diseases yet characterized. Specific requirements of successful gene delivery in this setting include correct targeting within tissue, durability, and a lack of immunogenecity. Progress toward this goal has advanced from identification of disease genes to reintroduction of wild-type genes to patient cell lines and primary cells in vitro. This initial work has been extended to gene-based correction of diseased tissue regenerated in vivo in the form of human patient skin xenografts on immune-deficient mice. Efforts in this human tissue model have laid the foundation for future efforts to extend this progress toward ex vivo cutaneous gene therapy trials in humans.