Globally, bodyweight and obesity are rising in both the developing and developed world. To maintain a stable bodyweight, energy intake must, over time, exactly equal energy expenditure, a state known as energy balance. An understanding of the physiologic control of energy balance may be useful for designing interventions to tackle the obesity epidemic worldwide. Obesity occurs when the body's energy balance is positive (i.e. when energy intake exceeds energy expenditure). Human physiology is biased toward maintaining energy balance at high levels of energy intake and expenditure. As a result, strategies to combat obesity should include a focus on increasing physical activity along with strategies for modifying food intake. An understanding of energy balance leads to the conclusion that prevention of weight gain should be easier than treatment of obesity. Components of energy balance are interdependent, and weight loss requires major behavior changes, which trigger compensatory decreases in energy expenditure that facilitate weight regain. Prevention of weight gain can be accomplished by smaller behavior changes. In addition to being easier to sustain than larger behavior changes, smaller ones produce less compensation by the energy balance regulatory system. It has been estimated that relatively small changes in energy intake and expenditure totaling 100 kcal per day could arrest weight gain in most people. Interventions that advocate small changes have shown promising levels of success.