A major effort has been on-going to develop immunotherapies to prevent and/or treat type 1 diabetes (T1D). This autoimmune disease is characterized by the selective loss of the insulin-producing β cells via the cumulative effects of autoantigen-specific CD4⁺ and CD8⁺ T cells, autoantibodies, and activated antigen-presenting cells. To be applicable in a clinical setting, immunotherapies must suppress established β-cell autoimmunity. Preclinical studies and recent clinical findings suggest that antigen-specific and systemic-based strategies can be effective in this regard. However, either approach alone may not be sufficient to block the diabetogenic response and establish long-term protection in the clinic. In this review, we will discuss the importance of both strategies and how a combinatorial approach to treat T1D is appealing.