Type 1 diabetes (T1D) is an autoimmune disease characterized by an insulin 
deficiency. Ever since the discovery of insulin almost 100 years ago, patients 
with T1D have relied on multiple daily insulin injections to survive an 
otherwise deadly disease. Despite decades of research and clinical trials, no 
treatment exists yet to prevent or cure T1D. A recent prevention trial using the 
anti-CD3 antibody teplizumab in individuals at a high risk of developing T1D has 
provided the first piece of evidence that a safe and transient intervention may 
be able to delay disease. In this Perspective, we review the 40-year long 
history of anti-CD3 and discuss how this antibody became a candidate for the 
treatment of autoimmune diabetes. The path that leads to its use in this latest 
clinical trial for T1D has been winding and strewn with setbacks. The molecular 
actions of the anti-CD3 antibody that target T lymphocytes are well-understood, 
but its systemic effect on immune function has proven more difficult to unravel. 
Moreover, preclinical data suggested that the utility of anti-CD3 for the 
prevention of T1D may be limited. However, the latest clinical data are 
encouraging and exemplify how a basic discovery can, decades later and with much 
perseverance, become a promising therapeutic candidate.