Many clinical studies have focused on the relationship between outcome events and serum 25- OH vitamin D levels, despite the fact that most effects are mediated by vitamin D receptor (VDR) activation, the most proximate ligand for which is 1,25-OH2 vitamin D. Evaluation of the separate components of this axis are well described, but an integrated view of the components, and the distinctions between the effects and consequences of substrate deficiency (25-OH vitamin D), and the direct effects of VDR activation, is the center of focus and ultimately impacts on the clinical approach to patents with chronic kidney disease (CKD). The focus of this contribution is on the specially defined need for vitamin D treatment in patients with CKD, and the importance of VDR activation in CKD, especially in patients with proteinuria. With the addition of the fibroblast growth factor-23 loop, and the realization that albuminuria represents several critical integrated levels of renal function, there is an emerging emphasis on the proximal tubule, interstitial inflammation and fibrosis. These interacting factors reflect fundamental mechanisms that culminate in progressive loss of kidney function(s), with loss of the glomerular filtration rate the most prominent feature. New therapeutic approaches could potentially intervene along these pathways, but they will have to be rigorously evaluated with defined outcome studies and cost-benefit ratio analyses. The ultimate impact of chronic renal replacement therapy and cardiorenal death are the measures by which all such innovations must be judged. Copyright © 2011 S. Karger AG, Basel.