The development of therapies that specifically target autoreactive immune cells for the prevention and treatment of type 1 diabetes (T1D) without inducing generalized immunosuppression that often compromises the host’s ability to clear non-self antigen is highly desired. This review discusses the mechanisms and potential therapeutic applications of antigen- specific T cell tolerance techniques using syngeneic apoptotic cellular carriers and synthetic nanoparticles that are covalently cross-linked to diabetogenic peptides or proteins through ethylene carbodiimide (ECDI) to prevent and treat T1D. Experimental models have demonstrated that intravenous injection of autoantigen decorated splenocytes and biodegradable nanoparticles through ECDI fixation effectively induce and maintain antigen-specific T cell abortive activation and anergy by T cell intrinsic and extrinsic mechanisms. The putative mechanisms include, but are not limited to, the uptake and processing of antigen-coupled nanoparticles or apoptotic cellular carriers for tolerogenic presentation by host splenic antigen-presenting cells, the induction of regulatory T cells, and the secretion of immunesuppressive cytokines, such as IL-10 and TGF-β. The safety profile and efficacy of this approach in preclinical animal models of T1D, including non-obese diabetic (NOD), BDC2.5 transgenic, and humanized mice, have been extensively investigated, and will be the focus of this review. Translation of this approach to clinical trials of T1D and other T cell-mediated autoimmune diseases will also be reviewed in this chapter.