Today, there are several observational and experimental studies, especially clinical randomized trials, that have proven the beneficial effects of n-3 polyunsaturated fatty acids (PUFAs). The most compelling evidence for the cardiovascular benefits of n-3 PUFAs comes from studies of primary prevention in patients following myocardial infarction, and most recently, in patients with heart failure. In this review, we analyze the evidence from epidemiologic studies and from large randomized controlled trials showing the benefits of n-3 PUFAs, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in primary and secondary cardiovascular prevention. Further studies are needed to determine optimal dosing and the relative ratio of DHA and EPA that provide maximal cardioprotection.