Why some patients with hemophilia A produce inhibitory antibodies is not known. However, many new findings both in the mechanisms of immune tolerance and in the understanding of the mechanisms by which antibodies interact with the factor VIII molecule are converging toward an integrated picture of what tolerance to factor VIII represents. The latter results from a subtle equilibrium among all partners of the immune system that is actively maintained. Circumstances under which such an equilibrium is disrupted are now better understood. The anti-factor VIII response can now be analyzed at the clonal level (both B and T levels), which allows us to test a number of hypotheses on both the prevention and the treatment of factor VIII inhibitors.