The development of inhibitory alloantibodies to factor VIII (FVIII) is a major complication of clotting factor replacement therapy for hemophilia A. Inhibitor development compromises effective hemostasis management in affected individuals and results in higher morbidity and costs of care compared with hemophilic individuals without anti-FVIII antibodies. The therapeutic approach to the management of bleeding in the presence of low- and high-titer inhibitors is founded on the principles of either saturating antibody with excess FVIII or bypassing the FVIII requirement altogether. Although spontaneous antibody disappearance does occur, immune tolerance is often required for antibody eradication. Studies aimed at optimizing this treatment approach and developing newer strategies for inhibitor prevention are ongoing.