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Peripheral tolerance is an important strategy used by the immune system to prevent self-reactive lymphocytes from attacking host tissues. A variety of mechanisms contribute to peripheral tolerance, among them activation-induced cell death, suppression by regulatory T cells, and T cell anergy or unresponsiveness. Recent work has led to a better understanding of the cell-intrinsic program that establishes T cell anergy. A major insight is that during the induction phase of anergy, incomplete stimulation (T cell receptor stimulation without costimulation) leads via calcium influx to an altered gene expression program that includes up-regulation of several E3 ubiquitin ligases. When the anergic T cells contact antigen-presenting cells, intracellular signaling proteins are monoubiquitinated and targeted for lysosomal degradation, thus decreasing intracellular signaling and also resulting in decreased stability of the T cell–antigen-presenting cell contact. We propose a molecular program leading to T cell anergy and discuss other proteins that may play a role.