Despite their clear therapeutic effects in coronary heart disease, use of n-3 polyunsaturated fatty acids (PUFAs) to treat other types of cardiovascular disease remains controversial, and serious obstacles exist in implementing them as a reliable and consistent drug therapy. The foremost of these is that a molecular mechanism and relevant dosages have not been firmly established in other forms of cardiovascular disease. In this brief review, we highlight the current state of knowledge regarding the mechanisms behind n-3 PUFA action in the cardiovascular system. We also propose the novel hypothesis that lipid peroxidation products derived from n-3 PUFAs may be driving much of their beneficial cardiovascular effects, particularly in the myocardium. We conclude by discussing evidence to support this hypothesis, and its possible clinical ramifications.