The use of anti-CD3 monoclonal antibodies (mAbs) has moved from the bench to the bedside. The experience with the anti-human CD3 mAb OKT3 for treatment of transplant rejection identified limitations that were largely overcome with the creation of humanized non-FcR binding antibodies: Teplizumab, Otelixizumab and Visilizumab. Preclinical studies showed the ability of the drugs to reverse hyperglycaemia in diabetic non-obese diabetic (NOD) mice providing rationale for clinical trials with the agents. The former two drugs have been tested in subjects with new onset type 1 diabetes. They have both shown, in randomized clinical trials, an ability to reduce the loss of insulin production over the first 2 years of the disease. In addition, the need for exogenous insulin to maintain glucose control has been reduced. However, these agents alone do not restore normal glucose control, and future approaches will likely require combinations of agents with complementary immune or metabolic activity.