Tolerogenic strategies that specifically target diabetogenic immune cells in the absence of complications of immunosuppression are the desired treatment for the prevention or even reversal of Type 1 diabetes (T1D). Antigen (Ag)-based therapies must not only suppress disease-initiating diabetogenic T cells that are already activated, but, more importantly, prevent activation of naive auto-Ag-specific T cells that may become autoreactive through epitope spreading as a result of Ag liberation from damaged islet cells. Therefore, identification of auto-Ags relevant to T1D initiation and progression is critical to the design of effective Ag-specific therapies. Animal models of T1D have been successfully employed to identify potential diabetogenic Ags, and have further facilitated translation of Ag-specific tolerance strategies into human clinical trials. In this review, we highlight important advances using animal models in Ag-specific T1D immunotherapies, and the application of the preclinical findings to human subjects. We provide an up-to-date overview of the strengths and weaknesses of various tolerance-inducing strategies, including infusion of soluble Ags/peptides by various routes of delivery, genetic vaccinations, cell- and inert particle-based tolerogenic approaches, and various other strategies that target distinct tolerance-inducing pathways.