Since the 2002 American Heart Association scientific statement “Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease,” evidence from observational and experimental studies and from randomized controlled trials continues to emerge to further substantiate the beneficial effects of seafood long-chain n-3 polyunsaturated fatty acids and cardiovascular disease. A recent American Heart Association science advisory addressed the specific effect of n-3 polyunsaturated fatty acid supplementation on clinical cardiovascular events. This American Heart Association science advisory extends that review and offers further support to include n-3 polyunsaturated fatty acids from seafood consumption. Several potential mechanisms have been investigated, including antiarrhythmic, anti-inflammatory, hematologic, and endothelial, although for most, longer-term dietary trials of seafood are warranted to substantiate the benefit of seafood as a replacement for other important sources of macronutrients. The present science advisory reviews this evidence and makes a suggestion in the context of the 2015–2020 Dietary Guidelines for Americans and in consideration of other constituents of seafood and the impact on sustainability. We conclude that 1 to 2 seafood meals per week be included to reduce the risk of congestive heart failure, coronary heart disease, ischemic stroke, and sudden cardiac death, especially when seafood replaces the intake of less healthy foods.