Despite the widespread use of statins in the setting of high cardiovascular risk, many patients continue to experience clinical events. This highlights the need to identify additional therapeutic strategies for high-risk patients. Interest in the use of omega-3 polyunsaturated fatty acids to prevent cardiovascular disease has been high for several decades. Despite promising results from before the statin era, many clinical trials have produced disappointing findings regarding products containing conventional doses of omega-3 fatty acids. More recent clinical trials using high doses of omega-3 fatty acids in targeted populations have suggested potential benefit when targeting the risk driven by atherogenic dyslipidemia. We review the clinical implications of completed and ongoing trials.