A variety of experimental approaches are currently being evaluated for controlling CD4+ T helper 1 (Th1)-mediated autoimmune pathology. Here, Stephen Miller and William Karpus compare and contrast the efficacies of various antigen-specific regulatory strategies. Particular emphasis is placed on the mechanisms of peripheral immune tolerance and how this may be used in the treatment and analysis of the pathologic T-cell repertoire in autoimmune and virus-induced demyelinating diseases.