For more than a decade, the Joint Center for Structural Genomics (JCSG) 1 has been at the forefront of developing tools and methodologies that allow the application of high-throughput structural biology to a broad range of biological and biomedical investigations. In the previous phases of the National Institutes of Health’s Protein Structure Initiative (PSI; 2000 to 2010) 2, we explored structural coverage of uncharted regions of the protein universe 3, as well as a single organism, allowing complete structural reconstruction of the metabolic network of Thermotoga maritima4. In the current phase (PSI: Biology; 2010 to 2015), the JCSG is leveraging its high-throughput platform to explore the structural basis for host-microbe interactions in the human microbiome. The emerging field of metagenomics has been particularly enlightening: the human gut microbiome sequencing projects have already uncovered fascinating new families and expansions of known families for adaptation to this environment. The gut microbiota is dominated by poorly characterized bacterial phyla, which contain an unusually high number of uncharacterized proteins that are largely unstudied. Their influence upon human development, physiology, immunity and nutrition is only starting to surface and is thus an exciting new frontier for structural genomics, where we can structurally investigate the contributions of these microorganisms to human health and disease. The JCSG is located at The Scripps Research Institute, the Genomics Institute of the Novartis Research Foundation, University of California at San Diego, the Sanford-Burnham Medical Research Institute and SSRL/Stanford University.