It is now well accepted that T helper cells play a central role in the induction and maintenance of autoimmune disease. Many experimental models have emphasized this fact and have illustrated the efficacy of therapeutic strategies aimed at disrupting T cell recognition of autoantigens. Antibodies directed at either class II proteins of the major histocompatibility complex (MHC) or CD4 accessory molecules have been universally successful. However, the potential use of antibodies for therapy in humans is complicated by host anti-globulin and anti-idiotype responses. An alternative approach to anti-MHC blockade with antibodies is peptide blockade of MHC molecules. In addition, peptides may be used as agonists of autoantigens in order to modulate the autoimmune response. The use of synthetic peptides for therapy is an innovative yet relatively unexplored approach and will be the subject for discussion in this article.