The pancreatic islet beta-cells are the target for an autoimmune process that eventually results in an inability to control blood glucose due to the lack of insulin. The different steps that eventually lead to the complete loss of the beta-cells are reviewed to include the very first step of a triggering event that initiates the development of beta-cell autoimmunity to the last step of appearance of islet-cell autoantibodies, which may mark that insulitis is about to form. The observations that the initial beta-cell destruction by virus or other environmental factors triggers islet autoimmunity not in the islets but in the draining pancreatic lymph nodes are reviewed along with possible basic mechanisms of loss of tolerance to islet autoantigens. Once islet autoimmunity is established the question is how beta-cells are progressively killed by autoreactive lymphocytes which eventually results in chronic insulitis. Many of these series of events have been dissected in spontaneously diabetic mice or rats, but controlled clinical trials have shown that rodent observations are not always translated into mechanisms in humans. Attempts are therefore needed to clarify the step 1 triggering mechanisms and the step to chronic autoimmune insulitis to develop evidence-based treatment approaches to prevent type 1 diabetes.