The natural tendency in T cell‐mediated autoimmune conditions to develop focused antigen‐specific responses that over‐utilize certain T cell receptor (TCR) V region segments prompts the induction of anti‐TCR‐specific T cells and antibodies that can inhibit the pathogenic T cells and promote recovery from disease. This natural regulatory network can be manipulated by injecting synthetic peptide vaccines that correspond to segments of the over‐expressed V genes. In experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis (MS), the pathogenic T cells are directed at myelin components, including basic protein (MBP). In some strains such as the Lewis rat and the PL/J mouse, the encephalitogenic BP‐specific T cells overexpress a particular V region gene (Vβ8.2) in their TCR. In vivo administration of Vβ8.2 peptides in rats or mice can prevent and treat EAE by boosting regulatory anti‐Vβ8.2‐specific T cells that inhibit but do not delete the encephalitogenic specificities. This regulation is mediated by soluble factors, suggesting that the presence of regulatory TCR‐specific T cells within the target organ (the central nervous system) may inhibit not only the stimulating Vβ8.2+ T cells, but also bystander T cells bearing different V genes. Parallel studies in MS patients have revealed striking V gene biases among BP‐specific T cell clones from some patients that provided a rationale for TCR peptide therapy. Injection of Vβ5.2 and Vβ6.1 peptides boosted the frequency of TCR peptide‐specific T cells and reduced responses to BP, in some cases with clinical benefit, indicating the presence of an anti‐TCR regulatory network in humans that may also be manipulated with TCR peptide therapy. © 1996 Wiley‐Liss, Inc.