This PhD research project aimed to explore some factors underlying the large inter-individual differences in physiological responses to hypoxia. Despite many investigations, assessment of hypoxic tolerance in healthy individuals is difficult and research fails to predict and differentiate well vs. poor responders. This PhD research partly answered this question by providing evidence of an individuals genetic potential to tolerate high-altitude hypoxia well (or poor). We have also shown that some molecular adaptations in muscle protein balance related to hypoxia depend on genetic factors, even though to a moderate extent. Besides the unmodifiable genetic sequence make-up, variable environmental factors also contribute to individual differences in hypoxic tolerance. We studied the influence of a nutritional factor, i.e. dietary nitrate supplementation, showing to partly offset the downregulation of functional capacity by high-altitude hypoxia. Understanding physiology at the limits of human tolerance to hypoxia is a worthy goal in itself but may in addition have considerable importance not only for healthy, but also patient populations. Further research into the genetic aetiology will enhance our potential to predicting hypoxic sensitivity.