The work examines the main mechanisms responsible for the process of acclimatization of the population of high mountain regions to the conditions of hypobaric hypoxia. The purpose of this review is to describe the pathways of genetic, epigenetic and physiological control in the adaptation of indigenous populations of highlands to reduced barometric pressure and oxygen tension in the environment. It has been shown that populations living in different high-mountain regions demonstrate different ways of adaptation in response to a decrease in the partial pressure of oxygen in the inspired air. The changes that occur in the body in response to stressful conditions are extremely diverse. These include changes in the respiratory, cardiovascular, hematological systems and cellular adaptation. In this review, we examine genomic variations leading to evolutionary adaptation to life at high altitudes, gene expression, pathophysiological and metabolic features, and long-term adaptation in various high-altitude populations. We also consider the peoples of the Caucasus as one of the most promising populations for further study of complex adaptation mechanisms.