Linoleic acid (LA) and alpha linolenic acid (ALA) belong to the n-6 (omega-6) and n-3 (omega-3) series of polyunsaturated fatty acids (PUFA), respectively. They are defined "essential" fatty acids since they are not synthesized in the human body and are mostly obtained from the diet. Food sources of ALA and LA are most vegetable oils, cereals and walnuts. This review critically revises the most significant epidemiological and interventional studies on the cardioprotective activity of PUFAs, linking their biological functions to biochemistry and metabolism. In fact, a complex series of desaturation and elongation reactions acting in concert transform LA and ALA to their higher unsaturated derivatives: arachidonic acid (AA) from LA, eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) from ALA. EPA and DHA are abundantly present in fish and fish oil. AA and EPA are precursors of different classes of pro-inflammatory or anti-inflammatory eicosanoids, respectively, whose biological activities have been evoked to justify risks and benefits of PUFA consumption. The controversial origin and clinical role of the n-6/n-3 ratio as a potential risk factor in cardiovascular diseases is also examined. This review highlights the important cardioprotective effect of n-3 in the secondary prevention of sudden cardiac death due to arrhythmias, but suggests caution to recommend dietary supplementation of PUFAs to the general population, without considering, at the individual level, the intake of total energy and fats.