Three models have been proposed to explain the inability of T lymphocytes to respond to self-antigens (reviewed in ¹): (a) self-reactive T cells are present but are prevented from functioning by suppressor T cells (suppression); (b) self-reactive T cells are present but have been functionally inactivated following interaction with host antigens (clonal anergy); and (c) self-reactive T cells are physically deleted (clonal deletion). A growing body of conclusive evidence indicates that clonal deletion is a major mechanism of tolerance induction for those antigens expressed in the thymus, the site of T cell development.^2–5 It is difficult, however, to understand how this mechanism could account for tolerance to tissue-specific antigens, expressed in low amounts outside of the thymus. A potential resolution to this paradox may be found in recent studies that provide in vivo evidence for a nondeletional mechanism of clonal anergy^6–8 that may operate outside of the thymus. The characteristics of the anergy observed in vivo are strikingly similar to those described for the induction of unresponsiveness in vitro for type 1 CD4⁺ T cell clones. Here we review our results on the induction of anergy in T cell clones and present new data on the mechanism by which it is maintained.