Proof-of-principle prenatal gene therapy studies have shown long-term expression of proteins at therapeutic levels and induction of immune tolerance in both small and large animals and cured congenital disease in some animal models. This chapter describes current progress with fetal gene therapy and discusses how this therapy may be eventually translated into the clinic. The genodermatoses may be good candidates for prenatal gene therapy, where gene transfer to the skin via the amniotic fluid may provide an obvious advantage to cumbersome postnatal therapy. Most of this work is performed in animals, mostly in mice that can provide transgenic models of human disease necessary to demonstrate proof-of-principle. The most commonly tested vectors in prenatal gene therapy pre-clinical studies have been adenovirus and adeno-associated virus, lentivirus and retrovirus vectors. Targeting of vectors to organs or specific tissues is the ultimate goal, and will most likely require the use of several combined approaches.