In fact, the danger theory has been often indicated as a possible explanation for the observed phenomena and together with the self/non-self theory it has been used to conceptualize the development of inhibitors in hemophilia A. However, recently, it has become evident that mechanisms of peripheral tolerance in post-natal life are also important in the balance between tolerance and immunity to FVIII, and in particular the role of two key immunoregulatory enzymes, HO-1 and IDO1, has been described. This evidence concerns the gene F8 and hemophilia A.