The development of a Factor VIII inhibitor, an antibody that blocks its procoagulant function, is one of the most serious complications of hemophilia A treatment. Similar antibodies are also recognized as a rare cause of bleeding in previously healthy individuals who develop autoimmune anti-Factor VIII antibodies. Recent studies have yielded important information about these antibodies in four different areas: better understanding of the incidence of inhibitors following Factor VIII treatment; identification of patients at highest risk of inhibitor formation; characterization of anti-Factor VIII; and the development of better therapies.