Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease in which the insulin producing β cells are destroyed. Antigen-based immunotherapy provides an approach to selectively tolerize pathogenic β cell-specific T cells, while leaving the remainder of the immune system intact. In this article, we discuss our group’s experience in defining the parameters that impact the efficacy of β cell antigen “vaccination” for the prevention and treatment of T1D.