Type 2 diabetes has become a major disease burden in China and globally. Thus, identifying high-risk individuals and elucidating the underlying mechanisms are crucial for the development of effective strategies to prevent type 2 diabetes. Metabolomics is a rapidly evolving technology and offers a new avenue for identifying novel biomarkers by assessing large numbers of metabolites that are substrates and products in metabolic pathways. Recent metabolomics studies in different populations have suggested that certain metabolites and metabolite classes may be associated with the risk of obesity, insulin resistance and type 2 diabetes. Using nested case-control studies within the Singapore Chinese Health Study and Dongfeng-Tongji Cohort, we have recently identified a number of novel metabolites that were significantly associated with development of incident type 2 diabetes in Chinese adults, such as increased branched-chain amino acids (leucine, isoleucine and valine), other amino acids (alanine, phenylalanine, tyrosine), non-esterified fatty acids (palmitic acid, stearic acid, oleic acid and linoleic acid), certain lysophosphatidylinositol (LPI) species and palmitoylcarnitine. With the rapid development of modern high-throughput “omics” technologies, such as genomics, epigenomics, and metabolomics, epidemiologists now can incorporate novel biomarkers at multiple levels into human observational studies, with the potential to shift the research paradigm from the traditional black-box strategy to a systems approach. Future research will need to harness the resources from large, well-powered population-based studies for initial discovery and validation of novel biomarkers by means of the “systems epidemiology” approach, in order to improve early disease detection, clinical diagnosis and prognosis, and contribute to personalized prevention and treatment.