Critically ill patients often suffer from hypoxaemia to which the response of the human body is far from understood. As this category of patients form a heterogenous group, they are difficult to study. In contrast to animal and cellular models, a new paradigm was suggested by the University College London (UCL) Centre for Altitude Space and Extreme Environment (CASE) Medicine, involving exposure of healthy volunteers to environmental hypobaric hypoxia in a controlled manner. This is based on the assumption that ascent to high altitude will trigger adaptive processes similar to the ones occurring in critically ill patients suffering from hypoxaemia, thereby obtaining better understanding of adaptive and maladaptive processes caused by hypoxaemia in a clinical context. In the spring of 2007 the medical research expedition Caudwell Xtreme Everest (CXE) took place on the slopes of Mount Everest in Nepal. Twentyfour investigator subjects (from a total of 60 investigators) and 198 volunteer subjects were studied over a period of three months. Specific hypotheses about oxygen delivery, oxygen consumption and metabolic efficiency were tested. Inter-individual responses to environmentally induced hypoxaemia were described and beneficial phenotypes and genotypes sought. In this article an explanation of this approach to hypoxia research along with an overview of the CXE expedition are presented. The results available to date are described in detail. Ultimately, the aim is to translate the knowledge obtained into further interventional research and practice in the clinical setting in the hope of improving the care of patients in whom hypoxaemia is a fundamental problem. © 2011, Nederlandse Vereniging voor Intensive Care.