In this article, the authors covered a number of issues that affect how researchers approach prevention of diabetes. The focus has been the use of cytokines and immunosuppressive therapies. The historical understanding of cytokine and immunosuppressive approaches, new developments in using these agents in humans, and the issues involved in designing diabetes prevention trials were reviewed. Although progress at times appears slow, the current research activities predict new developments in the next few years that may improve the understanding of the progression of diabetes and possible ways to intervene.