Type 1 diabetes begins with the progressive autoimmune mediated destruction of the insulin-producing beta cells. When sufficient beta cell function is lost, the endocrine phase, characterized by insulin deficiency and hyperglycemia, supervenes. While a genetic predisposition to diabetes is an important precondition, most believe an environmental factor or factors serve as the trigger for initiating this process. In this paper we review trials designed to prevent or delay the clinical onset of diabetes. In these studies, high-risk individuals are identified by their genetic predisposition to diabetes, and/or by the presence of immune markers indicating activation of the autoimmune process directed against islet cells. The Deutsche Nicotinamide Intervention Study (DENIS) randomized 55 high-risk subjects to either nicotinamide or placebo and found no significant benefit. The European Nicotinamide Diabetes Intervention Trial (ENDIT) completed enrollment in May 1998. ENDIT screened over 40 000 relatives, randomizing 552 to either nicotinamide or placebo. Results are expected in May of 2003. Designed to test if avoidance of cow's milk in infancy will decrease the incidence of diabetes, the Trial to Reduce Type I Diabetes in the Genetically at Risk (TRIGR). High-risk infants are randomly assigned to different supplemental formulas in the first 6 months of life. Initial results suggest that removing cow's milk has a protective effect. The ongoing, NIH funded, multicenter Diabetes Prevention Trial-Type 1 (DPT-1) is testing two antigen-based (insulin) interventions in relatives at high risk for diabetes. Now in its sixth year, the DPT-1 study group has screened over 84,000 individuals. As of November 2000, 339 subjects have been randomized in the parenteral insulin study, completing the enrollment phase. Enrollment continues in the oral insulin study. Results of this trial are not yet available. Different epitopes of insulin and its analogs, monoclonal antibodies, and cytokine-based therapy, among others, have all been proposed as potential new interventional agents. While a great deal of effort will be required to test these approaches, the potential benefits of prevention justify these research efforts.