Ascent to high altitude is accompanied by physiological responses that mitigate the challenge of hypobaric hypoxia, maintaining arterial blood oxygen content and convective oxygen delivery. At the tissues, oxygen utilisation also adjusts over time in response to altered oxygen availability through metabolic alterations that typically include a suppression of mitochondrial respiratory capacity and fatty acid oxidation. In lowlanders, acclimatisation can nevertheless result in compromised cellular energetics, yet studies in human populations of highland ancestry have revealed physiological traits, underpinned by genetic variants, that have undergone selection and which allow people to live, work and reproduce at high altitude. Of note, placental metabolic adaptations form a vital component of an integrated response that supports healthy pregnancies in highlander populations at altitude. Metabolic responses to tissue hypoxia have important implications for human health both at altitude and in human disease more generally, being associated with outcomes in critical ill patients and in common complications of pregnancy.