There is evidence from both observational studies and clinical trials that calcium malnutrition and hypovitaminosis D are predisposing conditions for various common chronic diseases. In addition to skeletal disorders, calcium and vitamin D deficits increase the risk of malignancies, particularly of colon, breast and prostate gland, of chronic inflammatory and autoimmune diseases (e.g. insulin-dependent diabetes mellitus, inflammatory bowel disease, multiple sclerosis), as well as of metabolic disorders (metabolic syndrome, hypertension). The aim of the present review was to provide improved understanding of the molecular and cellular processes by which deficits in calcium and vitamin D cause specific changes in cell and organ functions and thereby increase the risk for chronic diseases of different aetiology. 1,25-dihydroxyvitamin D3 and extracellular Ca++ are both key regulators of proliferation, differentiation and function at the cellular level. However, the efficiency of vitamin D receptor-mediated intracellular signalling is limited by the negative effects of hypovitaminosis D on extrarenal 25-hydroxyvitamin D-1α-hydroxylase activity and thus on the production of 1,25-dihydroxyvitamin D3. Calcium malnutrition eventually causes a decrease in calcium concentration in extracellular fluid compartments, resulting in organ-specific modulation of calcium-sensing receptor activity. Hence, attenuation of signal transduction from the ligand-activated vitamin D receptor and calcium-sensing receptor seems to be the prime mechanism by which calcium and vitamin D insufficiencies cause perturbation of cellular functions in bone, kidney, intestine, mammary and prostate glands, endocrine pancreas, vascular endothelium, and, importantly, in the immune system. The wide range of diseases associated with deficits in calcium and vitamin D in combination with the high prevalence of these conditions represents a special challenge for preventive medicine.