Autoimmune disease syndromes afict an estimated 50 million Americans, compared with 81 million with heart disease and 11 million with cancer . Among the autoimmune diseases, rheumatoid arthritis (RA), type 1 diabetes mellitus (T1D), multiple sclerosis (MS), inammatory bowel diseases (IBD), systemic lupus erythematosus (SLE), psoriasis, and scleroderma are the most common. According to estimates from the U.S. National Institute of Allergy and Infectious Diseases, autoimmune diseases contribute more than $100 billion to health care costs in the United States. These costs are rising as the prevalence of autoimmune diseases increases. The effect of autoimmune diseases in terms of human and health care costs emphasizes the urgency of dening the complex etiology and pathogenic mechanisms of autoimmune diseases, and translating these insights into effective autoimmune disease prevention and therapeutic strategies. Remarkable new data support the view that the vitamin D endocrine system performs a variety of critical biological functions that decrease the risk of autoimmune diseases, in particular MS, T1D, IBD, RA, and SLE (and possibly many more). By evaluating experimental data across several different human autoimmune diseases and their respective animal models from a vitamin D perspective, we aim at identifying both highly specic and common mechanisms of vitamin D hormone action that enable us to better understand the function of this important secosteroid hormone in vivo and harness its potential to both prevent and treat autoimmunity.