The review provides an evaluation of the therapeutic potential of vitamin D analogues in the context of the current understanding of vitamin D biochemistry, molecular biology and physiology. Vitamin D activity results from several circulating and intracellular physiological metabolites acting simultaneously through at least three receptors. Common analogues are reviewed. Although most vitamin D analogues have traditionally been analogues of 1,25-dihydroxyvitamin D, it may be better to deliver high doses of base vitamin or (analogues) of 25-hydroxyvitamin D. This would permit physiological endocrine, paracrine and autocrine vitamin D metabolism. Agonists or antagonists of tissue-specific vitamin D metabolic pathways could be coadministered. The importance of measuring endogenous vitamin D metabolites during in vivo studies and the pitfalls of extending data across species and time are emphasised. Human vitamin D analogue trials should include direct comparison against the related endogenous metabolite.