The physiological VDR ligand, 1α,25-dihydroxyvitamin D3, acts upon a wide variety of tissues and cells, both related to and unrelated to calcium and phosphate homeostasis. The noncalcemic actions of natural and synthetic VDR ligands are exemplified by their potent anti-proliferative, prodifferentiative and immunomodulatory activities. As a result, a VDR ligand is an approved drug for the topical treatment of psoriasis. A plethora of actions of 1α,25-dihydroxyvitamin D3 in various systems have suggested wide clinical applications of VDR ligands in such diverse disease states as inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, photoaging and skin rejuvenation), osteoporosis, cancers (breast, prostate, colon, leukemia and myelodysplastic syndrome) and autoimmune diseases (multiple sclerosis, type I diabetes and systemic lupus erythematosus). VDR ligands have shown therapeutic potential in limited human clinical trials as well as in animal models of these diseases. Some of the VDR ligands have shown not only potent preventive but also therapeutic anabolic activities in animal models of osteoporosis. However, the use of VDR in above mentioned indications as well as in oral therapy for psoriasis and even topical therapy for severe psoriasis is hampered by its associated toxicity, namely hypercalcemia. New VDR ligands have been synthesized which exhibit greater specificity by retaining desirable properties, but with reduced calcemic potential. The discovery of novel vitamin D3 analogs along with an increased understanding of the biological functions and mechanisms of action of VDR are likely to result in improved treatments for responsive indications.