Type 1 diabetes (T1D) satisfies many of the criteria for an autoimmune disease. The impact of the environment to promote the development of T1D and the ability to identify individuals at risk for T1D years before clinical presentation afford lessons for other autoimmune diseases, in regard to gene-environment interactions and the potential for rational approaches to pre-clinical diagnosis and prevention. Public health measures aimed at the modern pro-inflammatory environment are required to stem the rising tide not only of T1D but other autoimmune and chronic inflammatory disorders. In the non-obese diabetic (NOD) model of spontaneous autoimmune diabetes, compelling evidence indicates that adaptive autoimmunity to the pancreatic beta cell is initially targeted against proinsulin. Proof-of-principle studies in the NOD mouse, which established that insulin and proinsulin peptides could be applied as tools to induce immune tolerance and protect against diabetes development, await successful translation to at-risk humans. Initial trials of insulin-specific immunotherapy in humans show promise and reveal ways of optimising this approach that are also applicable to other autoimmune diseases.