Reestablishing immune tolerance in type 1 diabetes (T1D), a chronic autoimmune disease, is a major goal. The Immune Tolerance Network (ITN) has initiated eight clinical trials of immunomodulatory therapies in recent-onset T1D over the past decade. Results have been mixed in terms of clinical efficacy, but the studies have provided valuable mechanistic insights that are enhancing our understanding of the disease and are guiding the design of future trials. Trials of non-Fc-binding anti-CD3 mAb have revealed that modulation of the T cell target leads to partial responses, and ITN’s AbATE trial led to identification of a robust responder group that could be distinguished from non-responders by baseline metabolic and immunologic features. A pilot study of the combination of IL-2 and rapamycin gave the first demonstration that frequency and function of Treg cells can be enhanced in T1D subjects, although the therapy also triggered activation of effectors with transient β-cell dysfunction. Therapy with anti-thymocyte globulin (the START trial) led to substantial depletion of naïve and central memory CD4 and CD8 T cells, but also depletion of Tregs, no change in effector memory T cells, and activation of the acute phase response, with no clinical benefit at 12 months. In contrast, treatment with the anti-CD2 agent alefacept (the T1DAL trial) resulted in depletion of both central and effector memory T cells with preservation of Tregs and a signal of efficacy at 12 months. These results are providing biomarkers for safety and efficacy in future trials. For example, a positive Treg/Teff ratio appears to be critical for efficacy while a switch in the ratio correlates with lack of efficacy and may signal disease exacerbation. Furthermore, our results are delineating the roles of the major components of the immune response in T1D and are setting the stage for future combination therapy trials.