This thesis summarizes a research programme on the role of hypoxia-inducible factor (HIF) and its 2alpha subunit in systemic human physiology. Experiments were performed to assess the role of HIF in the regulation of skeletal muscle metabolism, cardiac anatomy, function and energy metabolism, and in cardiopulmonary physiology. Patients with different genetic mutations affecting the HIF pathway were recruited for each main study. Chapter 1 presents an overview of human physiological responses to hypoxia in a historical perspective, with particular attention to the areas of human physiology that are relevant for the studies presented in the experimental chapters. Chapter 1 also presents a summary of the HIF pathway and the novel findings presented in this thesis. Chapter 2 illustrates the methods used to perform the experiments. Chapter 3 investigates skeletal muscle metabolism, cardiac anatomy, function and energy metabolism in patients with Chuvash polycythaemia, who have mildly elevated levels of HIF, associated with a mutation in von Hippel-Lindau gene, at whole body level. Chapter 3 shows major abnormalities associated with HIF pathway alterations in skeletal muscle energy metabolism, especially in conditions of metabolic stress such as during exercise and digestion of a meal. Chapter 4 shows that patients with Chuvash polycythaemia also have small hearts and reduced cardiac energy levels. Chapter 5 explores cardiopulmonary abnormalities in patients with gain-of-function mutations specifically in HIF-2alpha subunit; these patients are polycythaemic like patients with Chuvash polycythaemia. Observed abnormalities include pulmonary hypertension, elevated heart rate, cardiac output, ventilation, and the increment in pulmonary blood pressure in response to moderate hypoxia. Chapter 6 presents results from experiments in patients with classic von Hippel- Lindau disease, who are not usually polycythaemic. However, some degree of haploinsufficiency was observed in their neutrophils, suggesting a pseudo-hypoxic phenotype. Chapter 6 shows that von Hippel-Lindau disease is not associated with major cardiopulmonary abnormalities. Overall, the research reported in this thesis presents original experimental evidence for the effects of alterations in the HIF pathway on human physiology.