The contribution of pathogenic infections to the etiology of autoimmune diseases remains one of the outstanding problems in immunology. According to the classical concept of antigen mimicry, a direct correlation between the incidence of autoimmunity and infections would be expected. This view is supported by a few examples of autoimmune disorders, which are documented as being caused by infection with particular pathogens. In contrast, there are several experimental animal models where infection appears to prevent the onset of autoimmunity. Moreover, some epidemiological studies suggest an inverse correlation between the incidence of autoimmunity and infections in human populations. Here we propose a solution to this puzzle based on a theoretical model of tolerance driven by regulatory T cells. The concepts here developed delineate the conditions predicting an inverse correlation between the incidence of autoimmunity and exposition to common infections, and those in which antigen mimicry and inflammation of target organs have a role in the etiology of specific autoimmune disorders.