Insulin-dependent type 1 diabetes mellitus (T1DM) is a chronic immune mediated disease in which T lymphocytes recognizing pancreatic islet cell antigens play a major role in the disease process [2, 3]. It has become increasingly clear that autoreactive T cells are important in the development and progression of this disease. The initial event in the pathogenesis of autoimmune disease is thought to be the priming of naïve autoreactive T cells, perhaps as a consequence of environmental exposure to shared epitopes (antigenic mimicry) or generalized inflammation/innate immunity [2-4]. Maximum activation of naïve T lymphocytes requires at least two independent signals. The first, an antigen-specific signal is sent via the clonotypic T cell receptor (TCR) which recognizes the appropriate peptide– MHC complex. The second signal, termed costimulatory signal, is independent of the antigen receptor and is critical to allow full activation. In addition, costimulatory signaling controls proliferation, prevents anergy and/or apoptosis, and induces differentiation to effector function and memory status. Costimulatory signals also regulate inhibitory receptors upon lymphocyte activation in a time-dependent manner [5, 6] It is now clear that the delicate balance of these positive and negative regulatory pathways underpins the outcome - self-tolerance versus autoimmunity . Therefore, the immune response observed in T1DM seems to be related to an imbalance of the sensitively regulated process which usually controls the activation of thymus-dependent lymphocytes. In this article, we summarize the role of costimulation in the development and progression of T1DM. In addition to the basic biology, we highlight important clinical advances in costimulation blockade that may impact this disease.