Purpose of Review: We discuss current controversies in the clinical use of omega-3 fatty acids (FA), primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and examine discrepancies between recent trials. Furthermore, we discuss potential side effects reported in these studies and the role of mixed omega-3 FA dietary supplements and concerns about their use. Recent Findings: REDUCE-IT showed that addition of icosapent ethyl, a highly purified form of EPA, can reduce risk of cardiovascular events among statin-treated individuals with high triglycerides. Additional supportive evidence for EPA has come from other trials and meta-analyses of omega-3 FA therapy. In contrast, trials of mixed EPA/DHA products have consistently failed to improve cardiovascular outcomes. Discrepancies in results reported in RCTs could be explained by differences in omega-3 FA products, dosing, study populations, and study designs including the placebo control formulation. Evidence obtained from highly purified forms should not be extrapolated to other mixed formulations, including “over-the-counter” omega-3 supplements. Summary: Targeting TG-rich lipoproteins represents a new frontier for mitigating ASCVD risk. Clinical and basic research evidence suggests that the use of omega-3 FA, specifically EPA, appears to slow atherosclerosis by reducing triglyceride-rich lipoproteins and/or inflammation, therefore addressing residual risk of clinical ASCVD.