The introduction of genes through the skin has been an attractive and dynamic field of research in recent years. It gives the first gleam of hope in therapy for the human genetic diseases that mainly affect this tissue, such as patients that suffer from xeroderma pigmentosum, and who experience increased frequency of skin cancer. The first in vitro experiments were successful in correcting the genetic defects of cells from these patients, the ex vivo reconstruction of corrected cells has been achieved, and the skin of model animals has been treated resulting in cancer prevention. Up to now these efforts have been possible, thanks to the high efficiency of viral vectors that provide gene delivery and expression targeted to many of the different skin cells, including those with proliferative and pluripotent features, such as keratinocytes and epidermal cells of hair follicles. Moreover, progress with several other methodologies qualifies them as alternatives to be explored, in some cases in combination with viral vectors, for skin gene therapy in these patients. Exciting and encouraging new approaches promise benefits to xeroderma pigmentosum patients and their families, and open perspectives of new ways for interfering in gene driven metabolism in the skin.