Although T cell tolerance to self antigens is primarily a reflection of clonal deletion in the thymus, recent evidence suggests that mature T cells are subject to negative regulation in the post-thymic environment: Extrathymic tolerance is the result of clonal anergy in some studies and T cell deletion in others. The factors controlling the induction of anergy versus deletion of mature T cells are still poorly understood. This article summarizes evidence that exposure of T cells to Mls superantigens in vivo leads to a sequence of T cell proliferation, anergy and deletion; anergy appears to reflect persistence of antigen. The biochemical consequences of exposing T cells to superantigens in vitro are discussed.