Hemophilia A is an X chromosome-linked recessive disorder resulting in defective or deficient factor VIII (FVIII) molecules, which, in its severe form, is a life-threatening, crippling hemorrhagic disease. Infusion of purified FVIII to patients with severe hemophilia A results in approximately 25% of the cases in the emergence of anti-FVIII antibodies (inhibitors) that are known to neutralize the procoagulant activity of FVIII by steric hindrance. We recently reported on the proteolysis of FVIII by alloantibodies in the plasma of two high responder patients with severe hemophilia A, demonstrating a new mechanism by which FVIII inhibitors may prevent the pro-coagulant function of FVIII. Hemophilia is the first model in which a direct link between the hydrolysis of the target molecule and the occurrence of clinical manifestations has been established. It also represents the first example in humans, of the induction of catalytic antibodies following the exogenous administration of an antigen. The characterization of FVIII inhibitors as site-specific proteases may provide new approaches to the treatment of inhibitors.