Factor (F) VIII is a large gene located near the terminus of the long arm of the X chromosome. It contains 26 exons that code for a signal peptide and a 2332 amino acid polypeptide with three different types of domains, namely A1-A2-B-A3-C1-C2. The A domains are homologous with each other and those of ceruloplasmin; substitution into the known crystal structure of the copper binding protein produces molecular models. The large, central B domain is highly glycosylated but has a variable sequence, even among FVIIIs from different species. Most of B can be deleted and the resulting recombinant protein has essentially normal survival in circulation and corrects the bleeding tendency in hemophilia A patients. The C domains are similar to each other, and the crystal structure of a recombinant human C2 domain is known, allowing construction of a molecular model of C1. The FVIII protein is secreted as a heterodimer following at least two intracellular cleavages within the B domain. In circulation it is stabilized by binding to von Willebrand factor (vWF) with a plasma half-life of about 10 hours. After specific thrombin cleavages that remove the remainder of the B domain and one of the high-affinity von Willebrand factor binding sites, FVIII becomes heterotrimeric FVIIIa, capable of enhancing intrinsic FX activation by FIXa. Inactivation of FVIIIa occurs by A2 dissociation or by specific cleavages within A1 and A2 by activated protein C. Control of intrinsic FX activation is critical for hemostasis and thrombosis.