The immune system is capable of recognizing any molecule that enters the body through a parenteral route. For that purpose, the lymphocyte population generates a large, diverse repertoire of receptors. Inevitably, many of these receptors recognize endogenous host antigens as well as exogenous molecules. Thus, self-reactive B cells and T cells are present in normal individuals and are potentially capable of producing an autoimmune response. The host consequently depends on certain mechanisms to avoid the harmful effects of autoimmunity. These mechanisms include negative selection in the thymus and bone marrow to delete the higher-affinity T and B cells and peripheral regulatory mechanisms, such as anergy, ignorance, and suppression. Despite such protective mechanisms, autoimmune diseases, collectively, are common in industrialized societies, even though individually most autoimmune diseases are rare. The diseases present differently depending on the site of pathology but share many fundamental mechanisms.