Hemophilia is a bleeding disorder that affects approximately 1 in 4000 males across populations worldwide. First-line therapy for the treatment of hemophilia is the intravenous administration of protein therapeutics to replace the deficient coagulation factor. However, in a significant number of patients, the immune system recognizes the therapeutic protein as 'dangerous' and mounts a humoral response that rejects the treatment and significantly increases the morbidity associated with this disease. Recent advances have been made in gene therapy in the field of hemophilia. Gene therapy provides the possibility of a cure for this disease; however, managing immunological tolerance to therapy is a challenge for this treatment modality. This review describes an approach in which gene therapy is used to deliver a tolerogenic construct to B-cells that can induce tolerance to protein therapy or to replacement gene therapy. Several other novel techniques to modulate immunity in patients with hemophilia, such as non-specific agents, mAbs and protein modifications, are at various stages of translation to the clinic and are also highlighted. The successful modulation of the immune system to accept treatment will significantly improve the quality of life for patients with hemophilia.