Hypoxemia elicits complex responses within the pulmonary circulation. Hypobaric hypoxia experienced at high altitude is well-tolerated in many individuals through acute and chronic adaptive responses. However, a minority of individuals demonstrate significant pulmonary vascular pathobiology manifesting as disease states such as high-altitude pulmonary edema (HAPE) and high-altitude pulmonary hypertension. These disease states are important to consider both as health risks to individuals living at or traveling to high altitude, as well as for the insights they provide into the pathobiology of pulmonary vascular disease associated with other disorders characterized by acute and chronic hypoxia.