Reports of a relationship between altitude and circulating levels of leptin suggest a possible role of hypoxia in leptin regulation. However, studies on the changes in plasma leptin levels at altitude are controversial with some showing an increase while others suggesting no change or a fall in these levels. Exposure to hypoxia has been shown to stimulate hypoxia-inducible factor 1 (HIF-1), which appears to be an important regulator for the expression of the leptin gene. However, there are a number of other variables that may influence the altitude-leptin relationship that could explain these divergent findings such as cold exposure, physical activity and diet, among others. Some of the studies presented suggest that hypoxia directly stimulates leptin release under controlled experimental conditions, whereas leptin levels may paradoxically decrease in response to certain physiological conditions associated with altitude. In conclusion, all confounding factors associated with altitude should be considered when assessing the leptin-altitude relationship.