The association between fish consumption and risk of cardiovascular disease (CVD) has been extensively studied. Although the results are inconsistent, the majority of studies are in favor of cardioprotective effects of fish consumption. There is little doubt that long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFAs) in fish are the key nutrients responsible for the benefits and are important for CVD prevention. Although fish is valued as a source of these fatty acids, it also provides other nutrients that may have cardioprotective effects. It is likely that the beneficial effects of fish consumption on the risk of CVD are the synergistic effects among nutrients in fish, and the integrative effects of fish consumption may reflect the interactions of nutrients and contaminants in fish. This review summarizes the epidemiology of fish or LCn-3PUFAs with major CVD risk factors as well as coronary heart disease mortality and stroke. This review also discusses the possible difference between whole fish as a nutrient package and fish oil supplements as a source of LCn-3PUFAs with respect to CVD prevention. Further studies are needed to investigate the potential adverse effects of contaminants in fish and the possible different effects from different types of fish and cooking methods.