In the immune system, many tolerance checkpoints exist to prevent self-antigens from stimulating the relentless growth of self-reactive B and T lymphocytes. The genes and molecular pathways underpinning these checkpoints overlap with those involved in tumor suppression. As with an inherited predisposition to cancer, inherited defects in self-tolerance genes typically precipitate autoimmune disease stochastically after a latent phase. Multiple mutations, inherited and somatic, may be needed before a self-reactive clone bypasses sequential tolerance checkpoints resulting in the emergence of autoimmune disease.