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Multiple randomized controlled trials (RCTs) have assessed the effects of supplementation with eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) known as omega-3 polyunsaturated fatty acids (FAs), commonly called fish oils, on the occurrence of cardiovascular diseases. In a living organism, omega-3 FA (EPA and DHA) and omega-6 FA (arachidonic acid [AA]) are also involved in the formation of key regulators of platelet aggregation, vasodilation and inflammation. It is important to know that EPA and DHA act in different ways on membrane structure and lipid metabolism. For this reason, combining DHA with EPA may modify the clinical effects of only EPA treatment. The effects of omega-3 FAs on cardiovascular system remain uncertain. Two recent negative trials of EPA + DHA, STRENGTH and OMEMI, have put the utility of omega-3 FAs in preventing atherosclerotic cardiovascular events under debate. This paper presents the actual knowledge on the role of polyunsaturated acids in cardiovascular diseases.