Tissue hypoxia arises when there is a mismatch between oxygen delivery and tissue metabolic demand. As such, hypoxia can result from exposure to environmental hypoxia e.g. hypobaric hypoxia at high altitude, or under pathological circumstances when convective oxygen supply to the tissues is perturbed. In highly oxidative tissues, such as the brain, this can challenge energetic and redox homeostasis, but is associated with metabolic responses that might mitigate this challenge. The hypoxia-inducible factor (HIF) pathway acts as a major regulator of the tissue response to hypoxia, controlling the expression of thousands of genes, including many genes involved in metabolic function. The characteristic metabolic response of tissues includes the suppression of mitochondrial respiratory function and increased glycolytic flux. Components of the HIF pathway including EPAS1 (encoding HIF2α) have undergone natural selection in populations native to high-altitude regions including the Tibetan Plateau and the Andean Altiplano. The brain metabolic response to hypoxia, and the role of the HIF-pathway, can therefore be understood, in part, through studies of lowlanders and adapted highlander populations undergoing acute exposure to hypoxia. Conversely, emerging evidence suggests that metabolic disease might influence brain oxygenation and metabolic function. Hypersecretion of the pancreatic hormone, amylin, is a feature of type 2 diabetes. Amylin aggregation has been associated with cerebrovascular dysfunction and brain accumulation of HIF1α and HIF2α in patients with Alzheimer’s Disease, with possible consequences for mitochondrial respiratory function and tissue energetics. This talk will consider the inter-relation of hypoxia, oxygen-sensing pathways and energy metabolism in the brain from these differing perspectives.