Although most recent research on energy balance focusses on energy intake (EI) there is still need to think about both sides of the energy balance. Current research on energy expenditure (EE) relates to metabolic adaptation to negative energy balance, mitochondrial metabolism associated with aging, obesity and type 2 diabetes mellitus, the role of EE in hunger and appetite control, non-shivering thermogenesis and brown adipose tissue activity, cellular bioenergetics as a target of obesity treatment and the evolutionary and ecological determinants of EE in humans and other primates. As far as regulation of energy balance is concerned there is recent evidence that EE rather than body weight is under tight control. Biologically, EE is maintained within a narrow physiological range. An EE-set point has been proposed as the width between the upper and lower boundaries of the individual EE range. Regulation of EE may fail in very obese patients with an EI above their upper boundary and after drastic weight loss when patients may go far below their lower EE boundary and thus are loosing control. In population studies, fat-free mass (FFM) and its composition (that is, the proportion of high to low metabolic rate organs) are major determinants of EE. It is tempting to speculate that tight biologic control of EE is related to brain energy need, which is preserved at the cost of peripheral metabolism. There is a moderate heritability of EE, which is independent of the heritability of FFM. In future, metabolic phenotyping should focus on the EE-FFM relationship rather than on EE-values alone.