Biomedical researchers in the 21st century work in the epicenter of an explosion in the understanding of human disease. The complete sequences of relevant genomes, like the human and various infectious organisms, lay the foundation for the next steps in probing molecular mechanisms of disease. Broad Institute researchers recognized at an early stage of this revolution that the perturbation of the cellular pathways that underlie phenotypic changes with small molecules will make it possible to dissect cell circuitry and disease biology, thus enabling a path forward to correcting human diseases. We have operated a Screening Facility in a production mode over the past ten years in an open data-sharing environment, created the first comprehensive and public small-molecule database and analysis environment containing over 20 million binding and assay-well measurements, a novel chemical biology information model and many powerful analysis tools, and, in 2007, made a substantial investment in personnel, screening automation, LIMS and robotics that has substantially increased these already significant production capabilities. This screening facility resides within a rich environment focused on small molecules and small-molecule screening integrated with disease biology and genome biology. We propose here a plan to operate a Comprehensive Screening Center at the Broad Institute of Harvard and MIT (BCSC), leveraging and complementing existing organizational and infrastructure initiatives by collaborating with a wider MLPCN research community.