High altitude exposure is often accompanied by weight loss. Postulated mechanisms are a reduction of nutritional energy intake, a reduction of intestinal energy uptake from impaired intestinal function and increased energy expenditure. Beyond the field of altitude, there are good reasons for renewed interest in the relationship between hypoxia and energy balance. The increasing prevalence of obesity and associated comorbidities represent a major health concern. Obesity is frequently associated with sleep disorders leading to intermittent systemic hypoxia with deleterious cardiovascular and metabolic consequences. Hypoxic regions may be present within hypertrophic white adipose tissue leading to chronic systemic inflammation. Among the increasing number of people commuting to altitude for work or leisure, obesity is a risk factor for acute mountain sickness. Paradoxically, exposure to intermittent hypoxia might be considered as a means to lose body mass and to improve metabolic risk factors. Daytime exposure to intermittent hypoxia has been used to treat hypertension in former Soviet Union countries and is now being experimented elsewhere. Such intermittent hypoxic exposure at rest or during exercise may lead to improvement in body composition and health status with improved exercise tolerance, metabolism and systemic arterial pressure. Future research should confirm whether hypoxic training could be a new treatment strategy for weight loss and comorbidities in obese subjects and elucidate the underlying mechanisms and signalling pathways.