Omega-3 polyunsaturated fatty acids (n-3 PUFAs) from fish and fish oils can protect against cardiovascular disease (CVD), which is still the most common cause of mortality and morbidity worldwide. To reduce CVD risk, integral lifestyle modifications, such as smoking cessation, moderate alcohol consumption, exercise, stress reduction, weight control, and diet, are needed. Evidence indicates that consuming fatty fish and n-3 PUFAs reduces the risk of CVD and mortality. Extensive randomized trials and meta-analyses have shown that high doses (1.8–4.0 g/day) of n-3 PUFAs are associated with a modest reduction in risk of myocardial infarction (MI) (−25%) as a secondary prevention, but not in the risk of all-cause mortality. However, the clinical outcomes of n-3 PUFAs are unequivocal, because their effects appear to depend on optimal background treatments (such as statins or antiplatelet agents) and specific patient groups. The optimal cutoff dose has not been established for the protective effects of n-3 PUFAs against CVD.