Maintaining energy balance in the context of body-weight regulation requires a multifactorial approach. Recent findings suggest that an elevated protein intake plays a key role herein, through (i) increased satiety related to increased diet-induced thermogenesis, (ii) its effect on thermogenesis, (iii) body composition, and (iv) decreased energy-efficiency, all of which are related to protein metabolism. Supported by these mechanisms, relatively larger weight loss and subsequent stronger body-weight maintenance have been observed. Elevated thermogenesis and GLP-1 appear to play a role in high protein induced satiety. Moreover, a negative fat-balance and positive protein-balance is shown in the short-term, whereby fat-oxidation is increased. Furthermore, a high protein diet shows a reduced energy efficiency related to the body-composition of the body-weight regained, i.e. favor of fat free mass. Since protein intake is studied under various energy balances, absolute and relative protein intake needs to be discriminated. In absolute grams, a normal protein diet becomes a relatively high protein diet in negative energy balance and at weight maintenance. Therefore 'high protein negative energy balance diets' aim to keep the grams of proteins ingested at the same level as consumed at energy balance, despite lower energy intakes.