Over the past four years, a remarkable sequencing technology explosion has occurred, openingmany new avenues of biological experimentation and discovery. We describe a platform for large-scale sequencing and analysis that extends the incredible potential of next-generationsequencing to transform biomedical research and significantly impact medical practice. Our eightspecific aims are intertwined across six major research areas that overall address the NHGRImission and provide an interdisciplinary approach that is already producing medically relevantresults in the areas of cancer genomics, heritable disease, and microbial/metagenomics. Ourplatform offers a consistently cost-effective approach to sequencing-related research projects andwe have established a scalable incoming sample pipeline that can intake and track >40,000samples per year into a flexible and innovative sequencing pipeline. Equally scalable are ourLIMS and analysis pipeline capabilities, having established systems that processed severalhundred cancer cases through whole genome sequencing and analysis in the last year alone,along with multiple other project types. We describe a research plan that will further ourexplorations of human health and disease, in a more comprehensive manner than ever before,and will investigate third-generation sequencing technologies, incorporating their unique attributesand integrating them to our production repertoire. One important aspect of our proposed workincludes efforts to begin translating our discoveries and procedures into the clinical setting,effectively setting the stage for genomic diagnosis and personalized medicine. This importanttransition will be required to bring DNA sequencing to clinical medicine, and our innovativecombination of sequencing technology, data analysis, and outstanding clinical collaboratorsincrease the potential for success. Overall, we are enthusiastic about the future of genomesequencing at high scale, and we combine years of success in DNA sequencing and analysiswith the necessary collaboration expertise, infrastructure support, and shared vision with NHGRIto make significant progress on these aims in the next four years.