Hypersensitive reactions to seafood is one of the most common food allergies. Despite years of intensive studies, the reasons why some people are allergic to seafood is still unclear. The growing demand for seafood and the subsequent increasing risk of seafood allergy in the population at large make it important to elucidate the molecular basis of seafood allergy and identify the seafood allergens at the molecular level. Here, we discuss the clinical symptoms, physiological mechanisms, current findings of the immunological and molecular basis of shellfish allergy as well as future directions for the prevention of shellfish allergy. Interestingly, identified seafood allergens belong to a group of muscle proteins, namely the parvalbumins in codfish and tropomyosin in crustaceans. In addition, there is strong immunological evidence that tropomyosin is a cross-reactive allergen among crustaceans and mollusks. The molecular cloning, expression and biochemical characterization of seafood allergens will continue to provide valuable tools in the further understanding of the mechanisms of seafood allergy as well as the future development of immunomodulation regimen.