Polyunsaturated fatty acids (PUFAs) particularly ω-3 PUFAs showed great assure in prevention of cardiovascular diseases (CVD). The evidence for CV benefits of PUFA comes from eicosapentaenoic acid (EPA) with or without docosahexaenoic acid (DHA) in primary prevention, after myocardial infarction (MI), with heart failure (HF). The epidemiologic studies and trials showing the benefits of PUFA, specifically EPA and DHA, in CV prevention and provide potential mechanisms. The target EPA and DHA consumption should be at least 500 mg/day for individuals without basic evident CV disease and at least 800 to 1,000 mg/day for individuals with known coronary heart disease (CHD) and heart failure (HF) and optimal dosing and relative ratio of DHA and EPA ω-3 PUFA that provides maximum cardio-protection at risk of CVD as well in treatment of atherosclerotic, arrhythmic, and primary myocardial disorders.