The bleeding disorder known as hemophilia B (HB) is caused by a deficiency or abnormality in the blood clotting factor IX (FIX) gene, which is inherited in an X-linked manner. This disease results from one of more than 1000 classified pathogenic variations in the FIX gene F9, and genetic missense and frameshift changes predominate. HB predominantly affects males, while heterozygous females may present with excessive bleeding resulting from random or nonrandom inactivation of the X chromosome. In addition, homozygous, compound heterozygous, and hemizygous females have been reported. Evidence of somatic and germinal mosaicism has been identified in F9 variants. The occurrence of antibodies to FIX therapeutic products (inhibitors) is rare and is influenced by the specific type of causative variation. Genetic therapy is currently undergoing clinical trials and involves the use of products produced by recombinant DNA technology. Heterozygotes, putative heterozygotes, and all affected individuals should receive genetic counseling that includes up-to-date information.