A primary focus in autoimmunity is the breakdown of central and peripheral tolerance resulting in the survival and eventual activation of autoreactive T cells. As CD4+ T cells are key contributors to the underlying pathogenic mechanisms responsible for onset and progression of most autoimmune diseases, they are a logical target for therapeutic strategies. One method for restoring self-tolerance is to exploit the endogenous regulatory mechanisms that govern CD4+ T cell activation. In this review, we discuss tolerance strategies with the common goal of inducing antigen (Ag)-specific tolerance. Emphasis is given to the use of peptide-specific tolerance strategies, focusing on ethylene carbodiimide (ECDI)-peptide-coupled cells (Ag-SP) and nonmitogenic anti-CD3, which specifically target the T cell receptor (TCR) in the absence of costimulatory signals. These approaches induce a TCR signal of insufficient strength to cause CD4+ T cell activation and instead lead to functional T cell anergy/deletion and activation of Ag-specific induced regulatory T cells (iTregs) while avoiding generalized long-term immunosuppression.