Scientists have been measuring energy expenditure by using gas exchange for the past 200 y. This technique is based on earlier work in the 1660s. Gas exchange in respirometers provides accurate and repeatable measures of resting metabolic rate. However, it is impossible to duplicate in a respirometry chamber the diversity of human behaviors that influence energy expenditure. The doubly labeled water technique is an isotope-based method that measures the energy expenditure of unencumbered subjects from the divergence in enrichments of 2 isotopic labels in body water--1 of hydrogen and 1 of oxygen. The method was invented in the 1950s and applied to small animals only until the early 1980s, mostly because of the expense. Since 1982, when the first study in humans was published, its use has expanded enormously. Although there is some debate over the precise calculation protocols that should be used, the differences between alternative calculations result in relatively minor effects on total energy expenditure estimates (approximately 6%). Validation studies show that for groups of subjects the method works well, but that precision is still relatively poor (8-9%) and consequently the method is not yet sufficiently refined to provide estimates of individual energy expenditures.