Nutritional metabolomics is rapidly maturing to use small-molecule chemical profiling to support integration of diet and nutrition in complex biosystems research. These developments are critical to facilitate transition of nutritional sciences from population-based to individual-based criteria for nutritional research, assessment, and management. This review addresses progress in making these approaches manageable for nutrition research. Important concept developments concerning the exposome, predictive health, and complex pathobiology serve to emphasize the central role of diet and nutrition in integrated biosystems models of health and disease. Improved analytic tools and databases for targeted and nontargeted metabolic profiling, along with bioinformatics, pathway mapping, and computational modeling, are now used for nutrition research on diet, metabolism, microbiome, and health associations. These new developments enable metabolome-wide association studies (MWAS) and provide a foundation for nutritional metabolomics, along with genomics, epigenomics, and health phenotyping, to support the integrated models required for personalized diet and nutrition forecasting.