Cardiovascular disease (CVD) is the leading cause of death in the USA. A diet enriched with n-3 fatty acids (FA) has been reported to play an important role in preventing the development of CVD. Prior studies have demonstrated beneficial effects of n-3 FA on hypertriglyceridemia, blood pressure, inflammation, endothelial function, and platelet function. However, data on the relation of n-3 FA consumption with CVD risk remain inconsistent. This paper reviews current evidence on the effects of n-3 FA on CVD, CVD risk factors, and potential biologic mechanisms. Last, we discuss major limitations of currently available data and future directions in the field.