Whereas high-avidity recognition of peptide-MHC complexes by developing T cells in the thymus results in deletion and promotes self-tolerance, such recognition by mature T cells in the periphery results in activation and clonal expansion. This dichotomy represents the basis of a dilemma that has stumped immunologists for many years, how are self-specific T cells tolerized in the periphery? There appear to be two important criteria used to achieve this goal. The first is that in the absence of inflammatory pathogens, tolerance is promoted when T cells recognize antigen presented by quiescent dendritic cells (DCs) expressing low levels of costimulatory molecules. A second critical factor that defines "self" and drives tolerance through deletion, anergy, or suppression is the persistence of antigen.