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It has now been established that differences in the risk of cardiovascular diseases, including atherosclerosis, exist between men and women. The field of nutritional genomics focuses on the interaction between diet and gene and consequent risk of disease. It is conceivable that advances in this area of investigation could result in specific dietary recommendations and guidelines to individual’s nutritional pattern as well as to populations at risk of cardiovascular abnormalities. Accordingly, this chapter will briefly describe and provide an update on sex dependent regulation of gene expression by different fatty acids in the diet in relation to heart disease risk. Such information could lead to novel sex-specific nutritional strategies for the management and prevention of cardiovascular disease.