Dietary fat and its relation to obesity has been a controversial issue for several years. In this review, several kinds of data relating to this issue are presented. There are epidemiological cross-country data and data within countries showing an effect. However, in the United States, the intake of fat appears to be declining, whereas the prevalence of obesity rises-the American Paradox. Clinical studies show that trans fatty acids can increase insulin resistance and that exercise can enhance the rate of adaptation to a high fat diet by increasing the rate of fat oxidation. The differences in response of inflammatory signals and of insulin resistance to different fatty acids indicate that not all fatty acids are the same. There are also experimental data showing that most, but not all, animals consuming a high fat diet will become obese. A number of mechanisms have been postulated for this difference, including differential sensitivities to neurotransmitters, to the intestinal peptide, enterostatin, and to individual fatty acids. One important conclusion from this review is that both total fat and individual fatty acids have to be considered when reaching conclusions about dietary fat and obesity.