At present, there is no cure for type 1A diabetes (T1D), a T cell-mediated autoimmune disease. Monoclonal antibodies (mAbs) are used to treat a wide number of diseases. For treating T1D, mAbs that target major immune cell subsets show considerable promise, but so far, when used at doses that do not cause unacceptable adverse reactions, have only been able to delay, but not prevent, disease progression. As a potentially safer alternative or adjunct, we have been investigating the utility of mAbs targeting defined peptide‒major histocompatibility complex (MHC) II complexes that are the ligands for disease-relevant CD4+ T cells. Alleles within the MHC class II locus confer the greatest genetic risk for T1D, and activation of pathogenic CD4+ T cells by antigen-presenting cells (APCs) expressing these ligands is central to disease etiology. Consequently, selective disruption of these critical interactions should arrest autoimmunity without causing global immunosuppression. Here, we review studies using an mAb targeting a key pathogenic epitope from insulin to treat a spontaneous mouse model of T1D and discuss the translational potential of therapies based on this approach.