There has been a resurgence of interest in the recognition and treatment of VDD beyond established roles in metabolic bone disease. Epidemiological studies implicate vitamin D and calcium homeostasis in a plethora of non-skeletal immune-based chronic diseases. Proposed mechanisms accounting for these pleiotropic actions focus upon well-characterised in-vitro immuno-modulatory effects, intracellular calcium signalling and the recent finding that the Vitamin D receptor is ubiquitous. The emerging science connecting biochemical deficiency, molecular or cytokine responses and disease pathogenesis is well-reviewed. VDD appears to predispose to vascular, rheumatic and neuropathic inflammation, hypertension, metabolic syndrome and atherosclerosis.