Vitamin D is a fat-soluble vitamin and a steroid hormone that plays a central role in maintaining calcium-phosphorus and bone homeostasis in close interaction with parathyroid hormone, acting on its classical target tissues, namely, bone, kidney, intestine, and parathyroid glands. However, vitamin D endocrine system regulates several genes (about 3 % of the human genome) involved in cell differentiation, cell-cycle control, and cell function and exerts noncalcemic/pleiotropic effects on extraskeletal target tissues, such as immune and cardiovascular system, pancreatic endocrine cells, muscle, and adipose tissue. Several studies have demonstrated the role of vitamin D supplementation in the prevention/treatment of various autoimmune diseases and improvement of glucose metabolism, muscle, and adipose tissue function. Hence, this review aims to elucidate the effects of vitamin D on extraskeletal target tissues and to investigate the potential therapeutic benefit of vitamin D supplementation among a broad group of pathological conditions, especially with regard to metabolic and autoimmune diseases. In addition, we focused on the best daily intakes and serum levels of vitamin D required for extraskeletal benefits which, even if still controversial, appear to be higher than those widely accepted for skeletal effects.