Viral infection has been hypothesized to be one of the environmental triggers for the development of type 1 diabetes. Infection induces a large amount of interferon-alpha (IFN-alpha) produced by dendritic cells and other cells. To test the role of IFN-alpha in the development of diabetes, we have used three different experimental approaches in both diabetes-prone and -resistant animal models for type 1 diabetes. Our results suggested that a viral mimic or IFN-alpha can either suppress or promote the development of autoimmune diabetes, depending on the model system. It is likely that IFN-alpha plays a complex role in the etiology of type 1 diabetes.