Patients with chronic renal failure frequently develop secondary hyperparathyroidism, primarily as a result of phosphate retention and low serum 1,25(OH)2D3. Replacement therapy with calcitriol or its synthetic precursor alfacalcidol [1α(OH)D3] often produces hypercalcemia, especially when combined with calcium-based phosphate binders. In addition, the natural vitamin D compounds can exacerbate the hyperphosphatemia in patients with chronic renal failure. This combined increase in calcium and phosphate has been correlated with vascular calcification leading to coronary artery disease, the most common cause of mortality in renal patients. Several vitamin D analogs have now been developed that retain the direct suppressive action of calcitriol on the parathyroid glands but have less calcemic activity, thereby offering a safer and more effective means of controlling secondary hyperparathyroidism. Maxacalcitol [22-oxa-1,25(OH)2D3] and falecalcitriol [1,25(OH) 2-26,27-F6-D3] are currently available in Japan, and paricalcitol [19-nor-1,25(OH)2D2] and doxercalciferol [1α(OH)D2] are available in the US. The mechanisms by which these analogs exert their selective actions on the parathyroid glands are under investigation. The low calcemic activity of maxacalcitol has been attributed to its rapid clearance from the circulation. This prevents sustained effects on intestinal calcium absorption and bone resorption, but still allows a prolonged suppression of parathyroid hormone gene expression. The selectivity of the other analogs is achieved by distinct mechanisms. Understanding how these compounds exert their selective actions on the parathyroid glands will aid in the design of safer, more effective analogs.