Type 1 diabetes (T1D) remains an important health problem, particularly in western countries, where the incidence has been increasing in younger children. In 1986, Eisenbarth described T1D as a chronic autoimmune disease. Work over the past three-and-a-half decades has identified many of the genetic, immunological and environmental factors that are involved in the disease and have led to hypotheses concerning its pathogenesis. Clinical trials have been conducted to test these hypotheses but have had mixed results. Here, we discuss the findings that have led to our current concepts of the disease mechanisms involved in T1D and the clinical studies promoted by these studies. The findings from preclinical and clinical studies support the original proposed model for how T1D develops but have also suggested that this disease is more complex than was originally thought and will require broader treatment approaches.