Establishing the safety of foods derived from genetically modified crops requires a multidisplinary approach using methods adapted from the biochemical, nutritional, toxicological and immunological sciences. The core principle of the process has been articulated as substantial equivalence, which is a comparative evaluation. Concerning potential allergens, it is essential to evaluate newly introduced proteins and when necessary, to evaluate potential changes in endogenous allergens. The incidence of food allergies appears to be on the rise, particularly in developed countries. Since no cure is available for those afflicted with food allergy, disease management is achieved by avoidance of the offending food. As a result, significant weight in the assessment is given to the need for prevention, which in the context of safety assessment, means reducing the likelihood of transferring offending allergens from one food source to another. Genetic engineering of food crops should have little practical consequence for the occurrence, frequency and natural history of food allergy if this evaluation is robust. Essential aspects of the assessment for allergenicity of genetically modified crops are discussed in this article.