An increase in dietary protein content may be positive for body weight regulation through effects on satiety, thermogenesis and substrate partitioning. Proteins may have insulinotropic effects as insulin is a major regulator of substrate metabolism, changes in its secretion may have a major impact on substrate oxidation. A crucial factor with respect to the effect of protein on diurnal insulinemic profiles, is whether a relative increase in dietary protein is obtained by a reduction of carbohydrate or fat. When protein replaces carbohydrate within a low-fat diet (reduced insulinemic and glycemic responses), fat oxidation may be increased. A shift in muscle substrate utilization from carbohydrate to fat oxidation in obese subjects may be positive for weight control and may be the impetus for improving insulin sensitivity. An additional issue, with respect to the potential positive effect of an increase in dietary protein, is the type of subjects studied. In type 2 diabetic subjects with a compromised response of the beta-cell to glucose, a protein-induced increase in insulin secretion may be beneficial to increase insulin-mediated glucose uptake, muscle mass and prevention of excessive glycemic and lipid overload in the systemic circulation. Nevertheless, in obese subjects the author proposes that minimizing diurnal insulin and glucose secretion, in the context of a low-fat diet (by increasing the protein/carbohydrate ratio of the diet), may represent an effective strategy for achieving and maintaining leanness, and improving insulin sensitivity through effects on substrate partitioning, favouring fat oxidation. Long-term dietary intervention studies are necessary to study the effect of a relatively increased dietary protein on body weight regulation and on the risk factors clustered in the metabolic syndrome.International Journal of Obesity (2006) 30, S24-S27. doi:10.1038/sj.ijo.0803488.