The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) in 2018 demonstrated the value of an omega-3 fatty acid formulation, icosapent ethyl (eicosapentaenoic acid ethyl ester) for preventive treatment of atherosclerotic cardiovascular disease (ASCVD). This JCL Roundtable discussion brings together three experts to explore the origins and implications of REDUCE-IT and more broadly omega-3 fatty acids for mitigation of ASCVD risk. REDUCE-IT achieved a highly significant 25% reduction of major adverse cardiovascular events. It is the first trial of a triglyceride-lowering drug to gain unequivocal success in high-risk patients treated intensively with statins. It corroborates positive results from an earlier major trial using eicosapentaenoic acid (EPA) ethyl ester, the Japan EPA Lipid Intervention Study (JELIS), which included hypercholesterolemic subjects treated with low-dose statin mostly in primary prevention. Together these studies mark a new avenue for preventive treatment of ASCVD. Omega-3 fatty acids also show some promise, though less decisively, for reducing inflammation and cardiovascular mortality in a broader context.