Persons with hemophilia A lack clotting factor (F)VIII (FVIII) due to a genetic mutation in the F8 gene. The administration of FVIII concentrate leads to the development of neutralizing anti-FVIII antibodies (inhibitors) in about 30% of children with severe hemophilia A. The other 70% of children do not mount a detectable antibody response, suggesting that they may have developed tolerance toward FVIII. Our knowledge on the underlying immunologic mechanisms that determine formation of inhibitors or apparent tolerance to FVIII is limited. Up to recently, FVIII concentrates were regularly used as prophylaxis. In the last years, nonfactor therapy for prophylaxis is increasingly used, in which case FVIII concentrate administration is limited to treatment for bleeding or perioperative hemostasis. As nonfactor therapy is very effective in the prevention of bleeds, patients may not be exposed to the deficient FVIII protein for periods up to a year or longer. Thus, while in the past persons with severe hemophilia were frequently exposed to the deficient antigen, exposure is now reduced to incidental treatment moments. It is currently not known how this will affect the tolerance for FVIII. In this review, we will discuss tolerance to FVIII from a clinical, immunologic, and epidemiologic perspective. We aimed to provide an outlook on the effect of reduced FVIII exposure on tolerance for FVIII in persons with hemophilia A.