Energy balance, i.e., the relationship between energy expenditure and energy intake is an important concept for human biology and health. The increasing prevalence of overweight and obesity in various populations has been attributed to a positive energy balance due to an increased energy intake or reduced energy expenditure. Despite considerable efforts, intervention programs addressing the problem of increased body weight lack efficiency. The lack of success with intervention studies trying to attenuate weight gain or accomplish weight reduction may be partially explained by compensatory responses to increased energy expenditure (exercise, lifestyle intervention) or reduced energy intake (diet). Various studies have shown that dietary intake can affect physical activity or the other way around. A negative energy balance also affects energy expenditure. Even though components contributing to energy expenditure, such as resting metabolic rate, exercise energy expenditure, non-exercise activity thermogenesis, and thermic effect of food as well as energy intake underlie a biological regulation they are also influenced by behavioural patterns. In addition, there is a complex relationship between these components in an effort to maintain energy balance. Results on compensatory behaviours in response to exercise or dietary interventions have been inconsistent but overall an increase in energy expenditure rather than decreased dietary intake seems to be a more promising approach in addressing the obesity epidemic. The purpose of this review is to highlight the complex interaction between various components contributing to energy balance in order to increase the understanding of the regulation of energy balance and thus body weight. This should be beneficial in the development of new programs or the adjustment of existing programs to address the current obesity epidemic.