The immune response to factor VIII and the development of inhibitory antibodies is a complex multi‐factorial process involving a variety of immune regulatory genes and cells, several of which have the potential to determine risk. A better understanding of the mechanisms involved will increase the likelihood of development of new therapeutic options for patients with hemophilia. This review summarizes genetic and non‐genetic risk factors currently under evaluation, and the potential modulative effect of the von Willebrand factor on factor VIII immuno‐ and antigenicity. In addition, the role of T‐regulatory cells in the pathogenicity of inhibitors will be discussed.