Observational cross-sectional and longitudinal studies suggest that a high fat diet and physical inactivity are independent risk factors for weight gain and obesity. Mechanistic and intervention studies support that fat possesses a lower satiating power than carbohydrate and protein, and a diet low in fat therefore decreases energy intake. The effect of dietary fat on energy balance is enhanced in susceptible subjects, particularly in sedentary individuals with a genetic predisposition to obesity who consume a high fat diet. Dietary carbohydrate promotes its own oxidation by an insulin-mediated stimulation of glucose oxidation. In contrast, high fat meals do not increase fat oxidation acutely. A sedentary life-style and low physical fitness cause a low muscular fat oxidation -capacity, and the consumption of a high fat diet by these individuals promotes fat storage in a synergistic fashion. Ad libitum low fat diets cause weight loss proportional to pre-treatment body weight in a dose-dependent way, i.e. weight loss is correlated positively to the reduction in dietary fat content. Increased physical activity prevents relapse after weight loss and studies have shown that those who keep up a higher level of physical activity are more successful in maintaining the reduced body weight. In conclusion, important interactions exist between genetic make up, dietary fat and physical fitness, so that a low fitness level and susceptible genes reduce muscular fat oxidation capacity which may decrease the tolerance of dietary fat. Increasing daily physical activity and reducing dietary fat content may be more effective when combined than when separate in preventing weight gain and obesity.