Hemophilia B, one of two common hereditary bleeding disorders, is caused by a deficiency of factor IX in the circulation. Molecular mechanisms of hemophilia B are highly heterogeneous including gene deletions, insertions, complex rearrangements, and a large number of point mutations. Currently, hemophilia B is treated by plasma protein replacement therapy. This therapy is effective but exposes patients to possible side effects and complications such as infection of blood-borne pathogens including hepatitis viruses and HIV-1. Intensive efforts to develop alternative, safer therapies for hemophilia B, including somatic gene therapy, are now under way.