Whole-genome sequences and their annotation have enabled the reconstruction of genome-scale metabolic networks. Such network reconstructions form the foundation for systems analysis of metabolic functions in health and disease. Over the past ten years, a series of genome-scale reconstructions have been built for microorganisms. They have been demonstrated to be useful for developing a deeper understanding of physiological processes, drive discovery through computer generated hypothesis relating to missing parts of a network, to interpret the consequences of gene knock outs, and for metabolic engineering and bioprocess purposes. With build-35 of the human genome sequence it has proved to be possible to initiate the build of a similar genome-scale reconstruction of metabolism in man. Thus an era of systems biology analysis of human metabolic functions has just been opened, in an analogous fashion as happened for microorganisms about 10 years ago. This proposal describes a program that will lead this new era. Our three overall objectives are: 1) to continue to build the metabolic reconstruction in an iterative fashion as has been done for microorganisms in the past, 2) to deploy existing computer algorithms to systematically fill in gaps in our knowledge base about human metabolism, and 3) to use the reconstruction high-throughput data analysis and to begin the effort of drug screening and discovery for metabolic interventions. The PI has been active in this field for over 25 years, and, in fact, has been a leader in developing reconstruction technology, the computer methods that are used to characterize them, and bring them to practical uses. He has been particularly active in training young scientist in this field and been involved in translational research and company startups.