Immunological self-tolerance is guaranteed by several complementary mechanisms arranged in a fail-safe hierarchy--namely, clonal deletion, inactivation, and suppression. Only failure of all these self-tolerance-preserving systems allows autoimmune disease to develop. The notion of such a fail-safe organisation of the immune system is compatible with several features of autoimmune disease: its multicausal nature, its slowly progressive and relapsing course, and the diverse range of interventions available to restore autotolerance. This hypothesis has practical implications for the understanding of both the pathogenesis of iatrogenic autoimmune disease and the design of strategies to re-establish self-tolerance.