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Type 1 diabetes is an autoimmune disease which occurs in (human leukocyte antigen) genetically predisposed individuals as a consequence of the organ-specific immune destruction of the insulin-producing β cells in the islets of Langherans within the pancreas. Type 1 diabetes is the result of a breakdown in immune regulation that leads to expansion of autoreactive CD4+ and CD8+ T cells, autoantibody-producing B lymphocytes and activation of the innate immune system.Islet-related autoantibodies revealed themselves to be good predictors of future onset of the disease, although they are not directly pathogenetic; T cells instead play a dominant role in disease initiation and progression. In this review, we first discuss the approaches that several laboratories attempted to measure human islet autoantigen-specific T-cell function in type 1 diabetes. T-cell assays could be used in combination with standardized autoantibody screenings to improve predictive strategies. They could also help to monitor in long-term follow-up the efficacy of tolerogenic immunotherapeutic strategies when established at the onset of the disease, and help to predict the recurrence of disease. Although some recent developments based on enzyme-linked immunosorbent spot and immunoblotting techniques have been able to distinguish with good sensitivity and specificity patients from controls, T-cell results, as revealed by international workshops, were indeed largely inconclusive. Nowadays, novel technologies have been exploited that could contribute to answering the tantalizing question of identifying autoreactive T cells. We particularly focus on and discuss MHC multimer tools and emphasize the advantages they can offer but also their weaknesses when used in combination with other T-cell assays. Copyright © 2011 John Wiley & Sons, Ltd.