High altitude constitutes an exciting natural laboratory for medical research. Over the past decade, the scope of high altitude research has broadened considerably, since it has become clear that the results of this research may have important implications, not only for the understanding of diseases in the millions of people living permanently at high altitude, but also for the treatment of hypoxemia-related disease states in patients living at low altitude. Studies in subgroups of subjects who do not adapt well to high altitude have greatly advanced our knowledge regarding underlying mechanisms predisposing to these diseases. High altitude pulmonary oedema is the best studied example of such a maladaptation. Here we will review recent work of our group that has provided novel insight in the pathogenesis of HAPE.