Decline in renal function is related directly to cardiovascular mortality. However, traditional risk factors do not fully account for the high mortality in these patients. Activated vitamin D, a hormone produced by the proximal convoluted tubule of the kidney, appears to have beneficial effects beyond suppressing parathyroid hormone (PTH). However, activated vitamin D also can cause hypercalcemia and hyperphosphatemia in chronic kidney disease. Newer agents such as vitamin D receptor activators (eg, paricalcitol) suppress PTH with reduced risk of hypercalcemia and hyperphosphatemia. Recent evidence from animal and preliminary human studies supports an association between vitamin D receptor activators and reduced risk of cardiovascular disease deaths, irrespective of PTH levels. New pathways of vitamin D regulation also have been discovered, involving fibroblast growth factor-23 and klotho. Although considerable work has been performed to advance our understanding of the effects of vitamin D in health and chronic kidney disease, more investigations and randomized trials need to be performed to elucidate the mechanistic underpinnings of these effects.