Recognition of the interplay between genes and diet in development of disease and for maintenance of optimal metabolism has led to nutrigenomic or nutrigenetic approaches to personalising or individualising nutrition, with the potential of preventing, delaying, or reducing the symptoms of chronic diseases. Some of the development work has focussed on cardiovascular disease or type II diabetes mellitus, where various groups have identified potential diet-gene interactions. However, the available studies also emphasise the exponential increase in numbers of subjects necessary to recruit for clinical evaluation if we are to successfully provide informative high-dimensional datasets of genetic, nutrient, metabolomic (clinical), and other variables. There is also a significant bioinformatics challenge to analyze these. To add to the complexity, many of the pioneering studies had assumed that single nucleotide polymorphisms (SNPs) were the main source of human variability, but an increasing evidence base suggests the importance of more subtle gene regulatory mechanisms, including copy number variants. As an example, the risk of Inflammatory Bowel Disease (IBD) is associated with the inheritance of a number of contributory SNPs as well as with copy number variants of certain other genes. The variant forms of genes often result in disruptions to bacterial homeostasis mechanisms or to signal transduction of the intestinal epithelial cell of the host, and thereby to altered intestinal barrier function, and/or adaptive immune responses. The human gut microbiota is altered in individuals suffering from disorders such as IBD, and probiotic or prebiotic therapies or elemental diets may be beneficial to a high proportion of individuals through modifying the gut microbiota, and also modulating immune responses. New putative foods or dietary therapies may be identified through novel tissue culture screens, followed by further testing with in vivo animal models of human disease. A scientifically based rationale for developing novel foods related to genotype might use a combination of food fractionation, testing in tissue culture models and validation through animal models, before moving into human populations. However, the field of nutrigenomics raises ethical, legal and social issues, and will be of genuine benefit to human health only if developed in linkage with adequately trained health professionals. Such training will widen public understanding, and permit dialogue with regulatory officials to responsibly develop, apply and progress this new field.