Extensive research demonstrates unequivocally that nutrition plays a fundamental role in maintaining health and preventing disease. In parallel nutrition research provides evidence that the risks and benefits of diet and lifestyle choices do not affect people equally, as people are inherently variable in their responses to nutrition and associated interventions to maintain health and prevent disease. To simplify the inherent complexity of human subjects and their nutrition, with the aim of managing expectations for dietary guidance required to ensure healthy populations and individuals, nutrition researchers often seek to group individuals based on commonly used criteria. This strategy relies on demonstrating meaningful conclusions based on comparison of group mean responses of assigned groups. Such studies are often confounded by the heterogeneous nutrition response. Commonly used criteria applied in grouping study populations and individuals to identify mechanisms and determinants of responses to nutrition often contribute to the problem of interpreting the results of group comparisons. Challenges of interpreting the group mean using diverse populations will be discussed with respect to studies in human subjects, in vivo and in vitro model systems. Future advances in nutrition research to tackle inter-individual variation require a coordinated approach from funders, learned societies, nutrition scientists, publishers and reviewers of the scientific literature. This will be essential to develop and implement improved study design, data recording, analysis and reporting to facilitate more insightful interpretation of the group mean with respect to population diversity and the heterogeneous nutrition response.