Xtreme Everest 2 (XE2) was part of an ongoing programme of field, laboratory and clinical research focused on human responses to hypoxaemia that was conducted by the Caudwell Xtreme Everest Hypoxia Research Consortium. The aim of XE2 was to characterise acclimatisation to environmental hypoxia during a standardised ascent to high altitude in order to identify biomarkers of adaptation and maladaptation. Ultimately, this may lead to novel diagnostic and treatment strategies for the pathophysiological hypoxaemia and cellular hypoxia observed in critically ill patients. XE2 was unique in comparing participants drawn from two distinct populations: native ancestral high-altitude dwellers (Sherpas) and native lowlanders. Experiments to study the microcirculation, mitochondrial function and the effect that nitric oxide metabolism may exert upon them were focal to the scientific profile. In addition, the genetic and epigenetic (methylation and histone modification) basis of observed differences in phenotype was explored. The biological samples and phenotypic metadata already collected during XE2 will be analysed as an independent study. Data generated will also contribute to (and be compared with) the bioresource obtained from our previous observational high-altitude study, Caudwell Xtreme Everest (2007).