Seafood is an important source of dietary protein worldwide, especially for coastal and island dwellers who now comprise 70% of the world’s population. Besides being high in protein and providing 40% of the world’s protein intake, seafood is low in cholesterol and saturated fatty acids and contains unique long-chain omega-3 polyunsaturated fatty acids (PUFAs). Two seafood PUFAs, eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) inhibit platelet aggregation and reduce mortality from myocardial infarction (MI) and ischemic stroke. Although the United States (U.S.) scientific community has recommended a Mediterranean-type diet, based on beneficial PUFAs in seafood, the European scientific community has cautioned that the increasing methylmercury levels in seafood may counteract any cardioprotective effects of PUFAs and actually increase risks of MI. This review describes the health benefits of seafood consumption and makes recommendations for the safe selection and preparation of seafood. In addition, this review describes the burden of seafood-borne diseases, separates seafood-borne toxic, heavy metal, and pesticide poisonings from seafood-borne infectious diseases; and makes recommendations for the management and prevention of seafood-borne illnesses. With the exception of some of the toxic seafood-borne illnesses, most seafood-borne infectious diseases, heavy metal poisonings, and pesticide poisonings can be prevented by careful selection and preparation of fresh seafood and adherence to weekly seafood consumption advisories, especially for those at highest risk of methylmercury poisoning, such as women who are pregnant, breastfeeding, or of child-bearing age, and children age seven and younger. A balanced diet combining protein from a variety of sources, including carefully selected and prepared seafood, along with natural antioxidants from fruits and vegetables is recommended to prevent seafood-borne diseases and to promote health and longevity.