Seafood is an important component in human diet and nutrition worldwide. However, seafood also constitutes one of the most important groups of foods in the induction of immediate (type I) food hypersensitivity, which significantly impacts the quality of life and healthcare cost. Extensive efforts within the past two decades have revealed the molecular identities and immunological properties of the major fish and shellfish allergens. The major allergen involved in allergy and cross-reactivity among different fish species was identified as parvalbumin while that responsible for shellfish (crustaceans and mollusks) allergy was identified as tropomyosin. The cloning and expression of the recombinant forms of these seafood allergens facilitate the investigation on the detailed mechanisms leading to seafood allergies, mapping of IgE-binding epitopes, and assessment of their allergenicity and stability. Future research focusing on the immunological cross-reactivity and discovery of novel allergens will greatly facilitate the management of seafood allergies and the design of effective and life-long allergen-specific immunotherapies.