Immune tolerance induction (ITI) is the most common approach used to eliminate inhibitors that develop in hemophilia A patients following exposure to factor (F) VIII therapy. ITI generally requires ongoing long-term exposure to factor replacement therapy using FVIII or FIX. Although plasma-derived products have been the mainstay of ITI therapy in the past, recent data indicate that high-purity (i.e., recombinant) rFVIII products are probably equally effective. For patients who have failed to respond to ITI treatment, or for those at high risk to do so, immunosuppressive therapy may be helpful. Rituximab has demonstrated a possible clinical benefit in hemophilic and nonhemophilic patients developing FVIII inhibitors, but benefit in those with congenital hemophilia and inhibitors has not been established and more extensive clinical studies are needed. More recently, research on reducing the incidence of inhibitor development has included mutagenizing key epitopes of the FVIII antigenic molecule to alter its immunogenicity without affecting biological activity, as well as induction of tolerance by gene therapy with immunodominant A2 and C2 domains of FVIII presented by B cells as immunoglobulin fusion proteins.