Abstract Nutrigenomics promises personalized nutrition and an improvement in preventing, delaying, and reducing the symptoms of chronic diseases such as diabetes. Nutritional genomics is the study of how foods affect the expression of genetic information in an individual and how an individual's genetic makeup affects the metabolism and response to nutrients and other bioactive components in food. The path to those promises has significant challenges, from experimental designs that include analysis of genetic heterogeneity to the complexities of food and environmental factors. One of the more significant complications in developing the knowledge base and potential applications is how to analyze high-dimensional datasets of genetic, nutrient, metabolomic (clinical), and other variables influencing health and disease processes. Type 2 diabetes mellitus (T2DM) is used as an illustration of the challenges in studying complex phenotypes with nutrigenomics concepts and approaches.