Most epidemiological studies indicate that obesity is more prevalent in populations consuming high fat diets. Furthermore, changes from a traditional to a westernized life style, characterized by a high-fat diet and decreased physical activity, result in dramatic increases in the prevalence and incidence of obesity in Native Americans, Pacific Islanders, and African populations. A possible explanation for the epidemic of obesity in response to high-fat intake can be found in the "oxidative hierarchy" that regulates macronutrient balance in the human body. Although carbohydrate and protein balances seem promptly regulated, fat balance is not. Short and midterm studies show that, unlike carbohydrate and protein intake, fat intake does not promote fat oxidation. Thus, "excess" fat intake results in fat deposition. As fat mass increases, so does fat oxidation, and a new equilibrium is reached when fat oxidation matches fat intake. However, there are large interindividual differences in this compensatory response to increased fat intake. Substrate oxidation is a familial trait, and individuals with a low fat-to-carbohydrate oxidation ratio are more prone to develop obesity than those with a high fat-to-carbohydrate oxidation ratio. Genetics may influence nutrient partitioning by influencing the activity of key enzymes of intermediate metabolism, such as lipoprotein lipase, beta-hydroxyl acyl CoA dehydrogenase, and acetyl CoA carboxylase.