Vitamin D receptor (VDR) agonists are well-known for their capacity to control calcium metabolism and to regulate growth and differentiation of many cell types. More recently, it has become clear that VDR agonists possess exquisite immunoregulatory properties, mostly by targeting dendritic cells and T cells. These properties have been exploited in the treatment of several Th1-mediated experimental autoimmune diseases, and a considerable body of work documents their beneficial effects in inhibiting the development of type 1 diabetes (T1D), a chronic-progressive autoimmune disease leading to the destruction of insulin-producing pancreatic β cells. This review analyzes the capacity of different VDR agonists to inhibit spontaneous T1D development in the non-obese diabetic (NOD) mouse, and shows that 1α,25-(OH)2-16,23Z-diene-26,27-hexafluoro-19-nor D3 (compound 6) is the most effective analog, among those tested, in delaying and reducing disease progression. Identified mechanisms of action underlying the efficacy of this VDR agonist in inhibiting T1D development in the NOD mouse are also reviewed.