Type 1 diabetes mellitus results from immune-mediated destruction of pancreatic β-cells, leading to loss of insulin production. Strategies to prevent or reverse diabetes development include β-cell protection, regeneration, or replacement. Recent advances in our understanding of the autoimmune process leading to diabetes has generated interest in the potential use of immunomodulatory agents that may collectively be termed vaccines, to prevent type 1 diabetes. Vaccines may work in various ways, including changing the immune response from a destructive (e.g. Th1) to a more benign (e.g. Th2) response, inducing antigen-specific regulatory T cells, deleting autoreactive T cells, or preventing immune cell interaction. To date, most diabetes vaccine development has been in animal models, with relatively few human trials having been completed. A major finding of animal models such as the non-obese diabetic (NOD) mouse is that they are extremely sensitive to diabetes protection, such that many interventions that protect mice are not successful in humans. This is particularly evident for human insulin tolerance studies, including the Diabetes Prevention Trial-1, where no human protection was seen from insulin despite positive NOD results. Further challenges are posed by the need to translate protective vaccine doses in mice to effective human doses. Despite such problems, some promising human vaccine data are beginning to emerge. Recent pilot studies have suggested a beneficial effect in recent-onset human type 1 diabetes from administration of nondepleting anti-CD3 antibodies or a peptide from heat shock protein 60. Given past experience, however, large multicenter, double-blind, controlled confirmatory studies are clearly required and longer term toxicity issues of drugs such as anti-CD3 need to be addressed. Diabetes vaccine development would benefit greatly from the development of reliable surrogate markers of immunoregulation. These would allow faster and more efficient screening of vaccine candidates, and would also assist in the translation of vaccine doses from animal to human studies. Unfortunately, research funding bodies desperate to find a cure are embarking on expensive clinical trials without first addressing important underlying issues such as animal-human dose translation and possible mechanisms of action. No doubt this is due to pressure from their constituency to rapidly find a cure, but unfortunately this approach may slow rather than speed the development of an effective vaccine cure. However, despite the significant hurdles that remain, vaccines remain one of the most promising strategies to prevent type 1 diabetes, with major advantages including convenience, safety, and long-lasting protection.