In the treatment of hemophilia A, the 20%-30% risk of developing of anti-factor VIII (FVIII) antibodies, or inhibitors, is the dominant concern among healthcare providers. Immune tolerance induction remains the only effective method of eradicating inhibitors in approximately 75% of patients, but is accompanied by significant emotional and economical burden. While certain risk factors, such as the type of FVIII mutation, offer some insight, there remains no strategy to confidently predict the development of an inhibitor. Moreover, even if such a predictive tool existed, there is currently no proven protocol for tolerance induction of a previously untreated patient. In recent years, the growing body of knowledge concerning the fundamental immunology of inhibitors has shed light on potential therapeutic interventions. In this review, we highlight these new findings and their influences on translational medicine.