pO2 in the kidney is maintained at relatively stable levels by a unique and complex functional interplay between renal blood flow, GFR, O2 consumption, and arteriovenous O2 shunting. The fragility of this interplay makes the kidney susceptible to hypoxic injury. Cells in the kidney utilize various molecular pathways that allow them to respond and adapt to changes in renal oxygenation. This review provides an integrative perspective on the role of molecular hypoxia responses in normal kidney physiology and pathophysiology, and discusses their therapeutic potential for the treatment of renal diseases.