Type 1 diabetes mellitus (T1DM) is a prototypic organ-specific autoimmune disease that results from selective destruction of insulin-secreting beta-cells by immune-mediated inflammation (insulitis), that is, the infiltration of pancreatic islets by autoreactive CD4(+) and CD8(+) T lymphocytes. Current treatment is substitutive-chronic use of exogenous insulin-which, in spite of considerable advances, is still associated with constraints and lack of effectiveness over the long-term in relation to the prevention of vascular and neurological complications. Finding a cure for T1DM is an important medical health challenge, as the disease's incidence is steadily increasing in industrialized countries and projections of future prevalence are alarming. Crucially, as T1DM mainly affects children and young adults, any candidate immune therapy must be safe and avoid chronic use of immunosuppressants that promote sustained depression of immune responses. The ideal approach would, therefore, involve induction or, in the case of established T1DM, restoration of immune tolerance to target autoantigens. This Review presents, in particular, two strategies that are still in clinical development but hold great promise. These strategies are focused on the use of candidate autoantigens and anti-CD3 monoclonal antibodies.