Renal parenchymal hypoxia has recently been documented in a host of clinical and experimental conditions characterized by tubulointerstitial changes and progressive chronic kidney disease (CKD). The nature of renal hypoxia under these settings, its causes and modes of detection are outlined in this review. Cellular hypoxia response, mediated in part by hypoxia-inducible factors (HIF), includes protective components, such as erythropoietin and heme-oxygenase-1, as well as the induction of harmful mediators. Prevention of the progression of CKD include strategies that attenuate renal parenchymal hypoxia, perhaps with selective intensification or inhibition of protective and harmful components, respectively of the hypoxia adaptive response.