In its most severe form, haemophilia A is a life‐threatening haemorrhagic bleeding disorder that is caused by mutations in the factor VIII (FVIII) gene. About 25% of patients who receive replacement therapy with intravenous FVIII products develop neutralising antibodies (FVIII inhibitors) that inhibit the function of substituted FVIII. Long‐term application of high or low doses of FVIII has evolved as an effective strategy for eradicating antibodies and inducing long‐lasting immune tolerance. Despite clinical experience with the therapy, little is known about the immunological mechanisms that cause the downmodulation of FVIII‐specific immune responses or the induction of long‐lasting immune tolerance against FVIII. This review summarises current knowledge of the immunological mechanisms that might be involved in the induction of immune tolerance against FVIII in patients with haemophilia A who have FVIII inhibitors. In addition to data from patients with haemophilia A, data from patients who have had organ transplants or have immune‐related disorders, such as autoimmune diseases, are considered as well as data from animal models.