Dietary fatty acids play significant roles in the cause and prevention of cardiovascular disease (CVD). Trans fatty acids from partially hydrogenated vegetable oils have well-established adverse effects and should be eliminated from the human diet. CVD risk can be modestly reduced by decreasing saturated fatty acids (SFA) and replacing it by a combination of polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA). Although the ideal type of unsaturated fat for this replacement is unclear, the benefits of PUFA appear strongest. Both n-6 and n-3 PUFA are essential and reduce CVD risk. However, additional research is needed to better define the optimal amounts of both and to discern the patients and/or general population that would benefit from supplemental n-3 fatty acid intake. Furthermore, consumption of animal products, per se, is not necessarily associated with increased CVD risk, whereas nut and olive oil intake is associated with reduced CVD risk. In conclusion, the total matrix of a food is more important than just its fatty acid content in predicting the effect of a food on CVD risk, and a healthy diet should be the cornerstone of CVD prevention.