Technological challenges relating to the large size of the F8 gene and inefficient expression of the human factor VIII coding sequence have been overcome with the development of a codon-optimized B-domain-deleted human F8 gene construct that can be delivered successfully by AAV [16]; and there is some preclinical evidence in both hemophilia A and hemophilia B to support the possibility that immunogenicity to transgene products can be overcome by directing gene transfer vectors to the liver to induce tolerance to preexisting factor inhibitors [17, 18]. This evidence concerns the gene F8 and hemophilia B.