Numerous epidemiological studies, case-control series, and randomized trials have demonstrated the ability of fish oil to reduce major cardiovascular events, particularly sudden cardiac death and all-cause mortality. We discuss the potential benefits of fish oil therapy to improve overall autonomic tone and potentially reduce the risk of major ventricular and atrial arrhythmias. Specifically, this review focuses on how fish oil therapy has performed in 3 primary prevention trials in patients with implantable cardioverter defibrillators, reviews the effects that fish oil has on the autonomic nervous system, focuses on the use of fish oil as a novel therapy for atrial fibrillation, and revisits other beneficial properties of fish oil (ie, ability to lower serum triglycerides, anti-inflammatory effects, and possible improvements in arterial pressure/diastolic function). We also discuss the safety profile of fish oil, including effects on bleeding time and bleeding complications as well as provide commentary regarding fish oil supplementation in light of increasing contaminants contained in fish. In summary, any patient with documented coronary heart disease and those with risk factors for sudden cardiac death, such as left ventricular dysfunction, left ventricular hypertrophy, prior myocardial infarction, or high-grade ventricular dysrhythmias, should consider fish oil supplementation. The American Heart Association recommends four 3-ounce servings of oily fish weekly. For those who cannot eat fish or do not have access to fish, as well as those who would prefer not to eat fish regularly, capsules of fish oil are readily available in various concentrations. At the present time, we recommend doses of eicosapentanoic acid and docosahexanoic acid in the combined range of 800 to 1000 mg/day for primary and secondary prevention of cardiovascular disease.