The ultimate goal of any treatment for autoimmune diseases is antigen- and/or site-specific suppression of pathology. Autoaggressive lymphocytes need to be eliminated or controlled to prevent tissue damage and halt the progression of clinical disease. Strong evidence is emerging that the induction of regulatory T (T_Reg) cells by autoantigens can suppress disease, even if the primary, initiating autoantigens are unknown and if inflammation is progressive. An advantage of these autoreactive T_Reg cells is their ability to act as bystander suppressors and dampen inflammation in a site-specific manner in response to cognate antigen expressed locally by affected tissues. In this review, we consider the nature and function of such antigen-specific T_Reg cells, and strategies for their therapeutic induction are discussed.