The safety assessment of food derived from genetically modified plants continues to attract considerable attention. Among the important issues that need to be considered is whether the products of novel genes introduced into crop plants will have the potential to induce allergic sensitization or to elicit allergic disease. Hierarchical approaches to allergenicity testing have been proposed, and these incorporate evaluation of the structural and sequence homology and serological identity of novel proteins with known allergens, measurement of resistance to proteolytic digestion, and assessment of allergenic potential using animal models. Accounts of these approaches are available elsewhere, and it is not the purpose of this article to provide a detailed critique of specific methods. Our intention is rather to look more broadly at the strategy for assessment of allergenic potential, the challenges such assessments pose for the practicing toxicologist, and how some of these might best be addressed.