Among inherited disorders, hemophilia has a number of characteristics that make it attractive as a model for gene transfer approaches. Several trials of gene therapy for hemophilia were carried out earlier in this decade; these trials were all first-in-class, i.e. the first use of a particular vector system in a particular target tissue, and thus yielded important safety data for the approaches under investigation. None, however, resulted in long-term expression of the clotting factor at therapeutic levels, and each encountered a critical issue, either in terms of safety, efficacy, or feasibility, that required further laboratory or clinical investigation. Ongoing trials of gene transfer for hemophilia include AAV-mediated gene transfer to liver using modified vectors (alternate serotypes, self-complementary constructs) or adjuvant therapies (transient immunosuppression). Preclinical studies using lentiviral vectors to transduce liver or hematopoietic cells have been promising, and genome editing and translational bypass strategies are also being investigated. Challenges to successful development of each strategy will be discussed.