Vitamin D compounds have been used successfully to treat secondary hyperparathyroidism for almost three decades. Side effects of increased levels of serum calcium and phosphate and potential complications have increasingly been recognized as problematic, and this has become an even more difficult clinical challenge with the desire to capitalize on some of the pleiotropic effects of vitamin D. Nonclassical nuclear vitamin D receptor (VDR) effects on the cardiovascular system, kidneys, and immune system, with the prospect of improved patient survival, have moved to center stage. Selective vitamin D compounds with minimal effects on mineral metabolism and with maximal cardiovascular and renal benefits are now needed. New vitamin D compounds already in clinical use, which have an improved side-effect profile and differential nonclassical effects compared with calcitriol, are limited to the three licensed pharmaceuticals--paricalcitol, 22-oxacalcitriol, and doxercalciferol. Other compounds are under early development and it is anticipated that these novel therapeutic concepts will result in new vitamin D therapies that will help to reduce the high mortality rate patients with kidney disease experience.