Exposure of mature CD4+ T cells in the peripheral immune system to peptide-antigen/MHC complexes in the absence of a threat of infection induces tolerance to the antigen as a result of both a decreased clonal frequency (peripheral deletion) and the induction of proliferative unresponsiveness (clonal anergy) in the survivors. Interestingly, Th 1-like effector functions are not automatically blocked after the development of clonal anergy. Thus, anergic T cells have the capacity to mediate Th 1-like helper activities if allowed to accumulate to high frequency. In this article, we examine those factors important to the development of tolerance versus immunity against protein antigen, and speculate on the relationship that exists between effective peripheral tolerance induction and the avoidance of autoimmune disease.