Non-Fc receptor binding anti-CD3 antibodies are in clinical development for the treatment of autoimmune diseases. Results from phase 1/2 clinical trials suggest that teplizumab and otelixizumab preserve residual beta-cell function in patients with recent onset type 1 diabetes. Similarly, encouraging results from phase 1/2 clinical trials have been reported for visilizumab and foralumab in patients with inflammatory bowel disease. However, these CD3-directed therapies have recently suffered setbacks due to the reported inefficacy results observed during phase 2/3 clinical trials due to low dosages or inappropriate clinical endpoints. Due to adverse events observed in the phase 1/2 pilot trials, the dose of anti-CD3 antibodies was reduced in the phase 2/3 confirmatory trials. Thus, these studies reveal a narrow therapeutic window of anti-CD3-based therapies in which low doses are ineffective and higher pharmacologically active doses cause intolerable levels of adverse effects. Combining anti-CD3 antibodies with other drugs may be the most effective way to reduce toxicity while allowing significant therapeutic benefit. Indeed, monotherapy also has its limits from the perspective of targeting only a single arm of the immune process. Notably, several recent experimental studies show potent synergy between anti-CD3 antibodies and various therapeutic modalities for the treatment of autoimmune diseases. In this review we present a review of preclinical studies evaluating combination therapies using anti-CD3 antibodies for the treatment of autoimmune diseases.