The nonobese diabetic (NOD) mouse is a well-recognised animal model of spontaneous autoimmune insulin-dependent diabetes mellitus. The disease is T-cell mediated, involving both CD4 and CD8 cells. Its progress is controlled by a variety of regulatory T cells. An unprecedented number of immunological treatments have been assessed in this mouse strain. This chapter systematically reviews most of these therapeutic manoeuvres, discussing them in the context of their significance with regard to the underlying mechanisms and the potential clinical applications. The contrast between the surprisingly high rate of success found for a multitude of treatments (more than 160) administered early in the natural history of the disease and the few treatments active at a late stage is discussed in depth. Most of the concepts and strategies derived from this model apply to other autoimmune diseases, for which no such diversified data are available.