Omega-3 polyunsaturated fatty acids (PUFAs) are a key component of a heart-healthy diet. For patients without clinical atherosclerotic cardiovascular disease, 2 or more servings of fatty fish per week is recommended to obtain adequate intake of omega-3 PUFAs. If this not possible, dietary supplementation with an appropriate fish oil may be reasonable. Supplementation with omega-3 PUFA capsules serves 2 distinct but overlapping roles: treatment of hypertriglyceridemia and prevention of cardiovascular events. Marine-derived omega-3 PUFAs reduce triglycerides and have pleiotropic effects including decreasing inflammation, improving plaque composition and stability, and altering cellular membranes. Clinical trial data have shown inconsistent results with omega-3 PUFAs improving cardiovascular outcomes. In this paper, the authors provide an overview of PUFAs and a summary of key clinical trial data. Recent trial data suggest the use of prescription eicosapentaenoic acid ethyl ester for atherosclerotic cardiovascular disease event reduction in selected populations.