Hemophilia A and hemophilia B are both X chromosome-linked recessive bleeding disorders that affect about 1 in 5000 males and result from a deficiency in the coagulation factors VIII and IX, respectively. Severely affected individuals require frequent administration of factor VIII or factor IX preparations derived from human plasma, and more recently, from recombinant DNA technology. Although these preparations have greatly reduced the contamination with blood-borne pathogens, there still exist significant limitations with protein replacement therapy. As we elucidate more about the expression, structure, and function of these coagulation factors new avenues will open for the development of novel genetically improved coagulation factors. Several aspects of the hemophilias A and B make these diseases attractive candidates for gene therapy. These advantages include the following: (1) these proteins are readily delivered into the circulation from a variety of different cell types; (2) low levels of expression would significantly improve the management of bleeding episodes in these patients; (3) it is unlikely that regulated expression of these proteins will be required; and (4) there are excellent animal models for these diseases. Although progress with gene transfer of factor IX has proceeded at a greater rate than factor VIII, success with both molecules has demonstrated partial persistent correction in mouse and canine models of hemophilia A and B. The information gained from these animal studies has provided new insights into gene therapeutic approaches for genetic diseases. In addition, several gene therapy clinical studies for the treatment of hemophilia A and B were initiated in 1999.