As a consequence of the general increase in allergic sensitization, the prevalence of hypersensitivity reactions to multiple foods that share homologous proteins has become a significant clinical problem. A variety of these allergens conserved among plants (eg, profilin and lipid transfer proteins) and animals (eg, tropomyosin and caseins) have been characterized. Although studies with molecular biologic techniques have elucidated the nature of these ubiquitous allergens, clinical studies have lagged behind. The physician is called on to determine the risk of reaction to related foods among legumes, tree nuts, fish, shellfish, cereal grains, mammalian and avian food products, and a variety of other plant-derived foods that may share proteins with pollens, latex, and each other. Clinical evaluations require a careful history, laboratory evaluation, and in some cases oral food challenges. The pitfalls in the evaluation of food allergy-unreliable histories and limitations in laboratory assessment primarily caused by false-positive skin prick test responses/RAST results are magnified when dealing with cross-reactive proteins. This review focuses on the clinical data regarding cross-reacting food allergens with the goal of providing a background for improved risk assessment and a framework on which to approach these difficult clinical questions.