Physiological responses to high altitude hypoxia are complex and involve a range of mechanisms some of which occur within minutes of oxygen deprivation while others reset a cascade of biosynthetic and physiological programs within the cellular milieu. The O2 sensitive events occur at various organisational levels in the body: at the level of organism through an increase in alveolar ventilation involving interaction of chemoreceptors, the respiratory control centers in the medulla and the respiratory muscles and the lung/chest wall systems; at tissue level through the pulmonary vascular smooth muscle constriction and coronary and cerebral vessel vasodilation leading to optimized blood flow to tissues; at cellular level through release of neurotransmitters by the glomus cells of the carotid body, secretion of erythropoietin hormone by kidney and liver cells and release of vascular growth factors by parenchymal cells in many tissues; at molecular level there is expression/activation of an array of genes redirecting the metabolic and other cellular mechanisms to achieve enhanced cell survival under hypoxic environment. Transactivation of various oxygen responsive genes is regulated by the activation of various transcriptional factors which results in expression of genes in a highly coordinated manner. There is thus an intricate cascading interplay of biochemical pathways in response to hypoxia, which causes changes at the physiological and molecular levels. Added to this interplay is the possibility of genetic polymorphism and protein changes to adapt to environmental influences, which may allow a variability in the activity of the pathway. Our understanding of these interactions is growing and one may be close to the precise combination of genetic factors and protein factors that underlie the mechanism of what goes on under high altitude hypoxic stress and who will cope at high altitude.