Birds that fly at high altitudes must support vigorous exercise in oxygen-thin environments. Here I discuss the characteristics that help high fliers sustain the high rates of metabolism needed for flight at elevation. Many traits in the O2 transport pathway distinguish birds in general from other vertebrates. These include enhanced gas-exchange efficiency in the lungs, maintenance of O2 delivery and oxygenation in the brain during hypoxia, augmented O2 diffusion capacity in peripheral tissues and a high aerobic capacity. These traits are not high-altitude adaptations, because they are also characteristic of lowland birds, but are nonetheless important for hypoxia tolerance and exercise capacity. However, unique specializations also appear to have arisen, presumably by high-altitude adaptation, at every step in the O2 pathway of highland species. The distinctive features of high fliers include an enhanced hypoxic ventilatory response, an effective breathing pattern, larger lungs, haemoglobin with a higher O2 affinity, further augmentation of O2 diffusion capacity in the periphery and multiple alterations in the metabolic properties of cardiac and skeletal muscle. These unique specializations improve the uptake, circulation and efficient utilization of O2 during high-altitude hypoxia. High-altitude birds also have larger wings than their lowland relatives to reduce the metabolic costs of staying aloft in low-density air. High fliers are therefore unique in many ways, but the relative roles of adaptation and plasticity (acclimatization) in high-altitude flight are still unclear. Disentangling these roles will be instrumental if we are to understand the physiological basis of altitudinal range limits and how they might shift in response to climate change.