The vitamin D endocrine system was originally discovered for its critical role in calcium and phosphate homeostasis. The active form of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol), promotes intestinal absorption of calcium and phosphate, but actions on bone, kidney and the parathyroids also contribute to the control of mineral metabolism. Subsequently, the vitamin D receptor (VDR) was detected in many other target tissues where calcitriol exerts pleiotropic effects, often in an autocrine/paracrine fashion. These non-classical activities of calcitriol have suggested therapeutic applications of calcitriol for the treatment of hyperproliferative disorders (e.g. cancer and psoriasis), immune dysfunction (autoimmune diseases), and endocrine disorders (e.g. hyperparathyroidism). In many cases, however, the effective therapeutic doses of calcitriol are hypercalcemic, a limitation that has spurred the development of vitamin D analogs that retain the therapeutically useful actions of calcitriol, but with reduced calcemic activity. Analogs with wider therapeutic windows are available for treatment of psoriasis and secondary hyperparathyroidism in chronic kidney disease, and research on even more effective analogs for these indications continues. Pre-clinical and clinical trials of analogs for treatment of several types of cancer, autoimmune disorders, and many other diseases are underway. Newer analogs show promise in various cellular models, but this review will focus on analogs currently in use and those with documented efficacy in animal models or in clinical trials.