The novel understanding that the presence of multiple islet autoantibodies, indicating islet autoimmunity, inevitably leads to type 1 diabetes mellitus (T1DM) has necessitated the development of a new staging classification system for the condition. Coupled with an improved understanding of the disease course, the realization that T1DM appears to be more heterogeneous than previously thought has led to unique opportunities to develop more targeted therapies that may be applied even before the onset of dysglycemia or symptoms. To date, several therapies have been trialed to delay or halt disease progression in both presymptomatic and clinical T1DM, each demonstrating varying degrees of effectiveness, toxicity, and utility. Key research supports the eventual implementation of immunotherapy in autoimmune diabetes, potentially calling for a paradigm shift among care providers. It will likely be necessary to develop new approaches to trial design and to address potential barriers to progress before an effective treatment for the disease may be achieved.