The negative selection of self‐reactive thymocytes depends on the expression of tissue‐specific antigens by medullary thymic epithelial cells. The autoimmune regulator (Aire) protein plays an important role in turning on these antigens, and the absence of even one Aire‐induced tissue‐specific antigen in the thymus can lead to autoimmunity in the antigen‐expressing target organ. Recently, Aire protein has been detected in peripheral lymphoid organs, suggesting that peripheral Aire plays a complementary role here. In these peripheral sites, Aire was found to regulate the expression of a group of tissue‐specific antigens that is distinct from those expressed in the thymus. Furthermore, transgenic antigen expression in extrathymic Aire‐expressing cells (eTACs) can mediate deletional tolerance, but the immunological relevance of Aire‐dependent, endogenous tissue‐specific antigens remains to be determined.