Cardiovascular disease (CVD) remains the major cause of death and disability worldwide, and residual risk after implementing all current therapies is still high. In this context, the latest (2016) European Cardiology Society/European Atherosclerosis Society guidelines recommend that triglyceride (TG)-lowering drugs should be used in high-risk patients with TGs levels >2.3 mmol/L (200 mg/dL), after lifestyle measures fail to lower them. After several neutral CVD outcome trials with n-3 fatty acids, the Reduction of Cardiovascular Events with EPA–Intervention Trial met its primary end point, that is, among patients with elevated TGs levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly lower in those who received 4 g of icosapent ethyl daily. In this review, we comment on the findings of previous and recently published randomized controlled CVD outcome trials assessing n-3 fatty acids supplementation. Both efficacy and safety, as well as future perspectives, are discussed.