More than 140 million people live permanently at high altitude (>2400 m) under hypoxic conditions that challenge basic physiology. Here we present a short historical review of the populating of these regions and of evidence for genetic adaptations and environmental factors (such as exposure to cobalt) that may influence the phenotypic responses. We also review some of the common renal physiologic responses focusing on clinical manifestations. The frequent presentation of systemic hypertension and microalbuminuria with relatively preserved GFR coupled with the presence of polycythemia and hyperuricemia suggests a new clinical syndrome we term high altitude renal syndrome (HARS). ACE inhibitors appear effective at reducing proteinuria and lowering hemoglobin levels in these patients. Copyright © 2011 by the American Society of Nephrology.