The High Throughput Screening Shared Resource (HTSSR) at Simmons Comprehensive Cancer Center (SCCC) allows SCCC members to translate cutting-edge discoveries in cancer research into new therapies and cancer-specific chemical tools. In the current project period, the HTSSR worked with 94 SCCC members across four research programs. These HTSSR-supported projects led to 41 new cancer-focused grants, 26 small molecule-related patents, and over 60 publications (51 cancer-focused) that appeared in top tier journals like Nature, Nature Communications, Cell, Science, Science Translational Medicine, Journal of the National Cancer Institute, Journal of Clinical Oncology, and others. These successes have been and continue to be heavily dependent on the extensive expertise and ready accessibility of the HTSSR personnel. Specifically, the director, Bruce Posner, PhD, and staff have over 50 years of combined expertise in screening small molecule and functional genomics libraries, supporting hit-to-lead optimization in preclinical drug discovery, and managing, visualizing, summarizing, and interpreting data from these activities. The HTSSR staff are all PhD-level scientists whose collective training spans high-throughput methods and assays, cell biology, biochemistry, bioinformatics, cheminformatics, data management, and structure-based drug design (SBDD). The Director and staff scientists are available at 100% effort to HTSSR activities, as is the instrumentation in the SR. The latter includes state- of-the-art instruments for high-content imaging of cancer cells and cell models, light-based assay detection of cell-based and biochemical systems, and high-throughput metabolite detection via mass spectroscopy. The HTSSR has expanded the chemical library, developed and optimized methods for 3D models of cancer, and is incorporating CRISPR screening into the arsenal of tools available to investigators. In the next project period, the HTSSR will (1) continue to improve expertise and infrastructure to meet SCCC members’ needs, (2) build out the chemical screening library with new compounds and retire parts of its old library that are nearing end of life, (3) actualize centralized CRISPR screening for SCCC members (pooled and arrayed), (4) explore new cheminformatics and bioinformatics methods that utilize artificial intelligence and machine learning, and (5) work with SCCC members on cancer cell models that reflect the tumor microenvironment for targeted and immunotherapy-driven SCCC projects. In sum, the HTSSR provides valuable support and expertise to SCCC members, who focus on taking innovative research from the bench to the bedside.