Humans have lived at high altitude for thousands of years despite the unavoidable stress imposed by low oxygen (hypoxia). Our work takes an integrative physiological genomics approach to understand adaptative and maladaptive variation in populations from the Tibetan Plateau, Andes, and Ethiopian highlands. Our team further aims to integrate physiological, molecular, and genetic aspects of hypoxia responses in high-altitude adapted populations to better understand how natural variation within our species aids or impedes hypoxia challenges inherent to many common disease states.