Abstract This proposal requests funds for the acquisition of a X-ray diffraction system that will meet the present and future on-site needs of a group of NIH-funded investigators located on the Charles River and Medical Campuses of Boston University. The proposed instrument will replace an eleven-year-old Bruker X8 Proteum-R diffractometer system which is reaching the end of its service life (no parts/service plan available after June 2020). We propose to purchase and install a new instrument featuring a reliable, low maintenance X-ray source and a state-of-the-art detector. Bruker’s IµS DIAMOND Cu source runs at low power and is air-cooled, yet the X-ray intensity surpasses the intensity of the existing rotating anode X-ray source. The proposed Photon III M28 CPAD detector will provide greatly improved sensitivity for weakly-diffracting samples and data collection at least five-fold faster via shutterless image acquisition capability. The new instrument will perform better for protein screening and data collection for macromolecular and small-molecule crystals. The vastly improved performance for small molecules based on faster screening time to identify target specimens will enable greater productivity through better data quality in terms of signal-to-noise, and enhanced speed of data collection. The fast data collection time allows determination of the connectivity and relative stereochemistry of small molecules with a speed rivaling that of NMR. The system will allow the determination of macromolecular structures and complexes with ligands and improve data quality of small or weakly diffracting crystals through use of the microfocus source and large-format detector, which allows for enhanced spatial resolution of the diffracted rays. Data collection will be optimized by utilizing the automated goniometer head to find the optimum crystal volume to expose, an impractical task using the coarse manual goniometer wrenches on the typical goniometer. The ISX plate-handling stage will allow in situ screening and data collection for mechanically sensitive crystals without harvesting from crystallization plates, and allow automated plate screening, maximizing users' work productivity for large screening jobs. These capabilities, which will afford improved throughput and data collection for samples that were previously unusable, will greatly support and enhance the NIH-funded projects of the five major and six minor users. The research topics include intervention in protein-protein interactions in immunodeficiencies; defining bacterial biosynthetic pathways; accelerating general anesthetic discovery; muscle regulation; redox regulation; natural products as therapeutics; synthesis of tunable organic semiconductors, and synthetic polysaccharides for drug delivery and to restore the properties of osteoarthritic cartilage.