The use of whole-food (grain meal contained in feed) animal-feeding studies to support the safety assessment of genetically modified crops has been contentious. This may be, in part, a consequence of poorly agreed upon study objectives. Whole-food animal-feeding studies have been postulated to be useful in detecting both expected and unexpected effects on the composition of genetically modified crops. While the justification of animal feeding studies to detect unexpected effects may be inadequately supported, there may be better justification to conduct such studies in specific cases to investigate the consequences of expected compositional effects including expression of transgenic proteins. Such studies may be justified when (1) safety cannot reasonably be predicted from other evidence, (2) reasonable hypothesis for adverse effects are postulated, (3) the compositional component in question cannot be isolated or enriched in an active form for inclusion in animal feeding studies, and (4) reasonable multiples of exposure can be accomplished relative to human diets. The study design for whole-food animal-feeding studies should be hypotheses-driven, and the types of data collected should be consistent with adverse effects that are known to occur from dietary components of biological origin.