Exposure to hypoxia elicits widespread physiological responses that are critical for successful acclimatization; however, these responses may induce apparent maladaptive consequences. For example, recent studies conducted in both the laboratory and the field (e.g. at high altitude) have demonstrated that endothelial function is reduced in hypoxia. Herein, we review the several proposed mechanism(s) pertaining to the observed reduction in endothelial function in hypoxia including: (i) changes in blood flow patterns (i.e. shear stress), (ii) increased inflammation and production of reactive oxygen species (i.e. oxidative stress), (iii) heightened sympathetic nerve activity, and (iv) increased red blood cell concentration and mass leading to elevated nitric oxide scavenging. Although some of these mechanism(s) have been examined in lowlanders, less in known about endothelial function in indigenous populations that have chronically adapted to environmental hypoxia for millennia (e.g. the Peruvian, Tibetan and Ethiopian highlanders). There is some evidence indicating that healthy Tibetan and Peruvian (i.e. Andean) highlanders have preserved endothelial function at high altitude, but less is known about the Ethiopian highlanders. However, Andean highlanders suffering from chronic mountain sickness, which is characterized by an excessive production of red blood cells, have markedly reduced endothelial function. This review will provide a framework and mechanistic model for vascular endothelial adaptation to hypoxia in lowlanders and highlanders. Elucidating the pathways responsible for vascular adaption/maladaptation to hypoxia has potential clinical implications for disease featuring low oxygen delivery (e.g. heart failure, pulmonary disease). In addition, a greater understanding of vascular function at high altitude will clinically benefit the global estimated 85 million high altitude residents. (Figure presented.).