Type 1 diabetes mellitus (T1DM) is an autoimmune disease affecting 3 million individuals in the U.S. The pathogenesis of T1DM is driven by immune-mediated destruction of pancreatic β cells, the source of glucose regulator insulin. While T1DM can be successfully managed with insulin replacement therapy, approaches that can modify the underlying immuno-pathology of β cell destruction has been long sought after. Immunotherapy can attenuate T cell responses against β cell antigens. Given the detailed cellular and molecular definitions of T1DM immune responses, rational immunomodulation can be and have been developed in mouse models, and in some instances, tested in humans. The possibility of identifying individuals who are predisposed to T1DM through genotyping lend to the possibility of preventive vaccines. While much has been accomplished in delineating the mechanisms of immunotherapies, some of which are being tested in humans, long-term preservation of β cells and insulin independency has not been achieved. In this regard, the drug delivery field has much to offer in maximizing the benefits of immune modulators by optimizing spatiotemporal presentation of antigens and costimulatory signals. In this review, we attempt to capture the current state of T1DM immunotherapy by highlighting representative studies.