Developing therapies to stop or slow the immune destruction of islets has been a goal of investigators in type 1 diabetes for several decades. This review of clinical interventions in patients with type 1 diabetes indicates both negative and positive outcomes with a variety of different therapeutic agents. An underlying theme of this article is that differences in study design may impact the outcome more than the therapy being tested. Thus, each of these results need to be considered in the context of important variables in study design. To date, there is no clear answer as to what study design is best to determine if an agent is effective against the diabetes disease process; however, the Immunology of Diabetes Society has recently developed guidelines for the conduct of these trials to facilitate comparisons of therapies in the future.