SUMMARY The emergence of SARS-CoV-2 into a worldwide pandemic has accounted for > 4,800,000 deaths worldwide, has exposed the dearth of antiviral therapeutics needed to control, treat and prevent infections from viruses of pandemic potential. Despite the successful development and deployment of multiple vaccines with high efficacy, vaccine hesitancy and continued emergence of escape mutants have undermined disease control and placed an urgent need for small-molecule medicines to supplement vaccines. Within this proposal, high throughput target-based and cell-based screening approaches are being pursued to provide a comprehensive drug discovery program to identify direct-acting antivirals. The Center for Antiviral Medicines and Pandemic Preparedness (CAMPP) High-throughput Screening (HTS) Core (Core A) will coordinate and execute the screening of Scripps Calibr’s >800,000 small molecule probe libraries which includes focused antiviral collections, propriety fully functional fragment libraries, access to DNA-encoded libraries and chemically diverse, small-molecule libraries. This will lead to the identification of validated screening hits and execution of hit follow- up studies in coordination with the Medicinal Chemistry Core. Essential to the success of CAMPP is the HTS core’s ability to support internal and external screening by managing small molecule probe libraries, screen data, compound follow-up and medicinal chemistry support. The HTS Core has extensive experience with each of those functions, managing > 352 internal and external screens in its nine years of existence. This includes a fully established compound management team, scientists to complete initial assay optimization (or transfer from a collaborator with antiviral expertise), developing miniaturized (384- and 1536-well) assays using fluorescent, luminescence or high-content imaging readouts in addition to data analysis, storage and dissemination among team members. The HTS Core also has a fully enabled BSL3 workflow to evaluate and characterize antiviral activity against SARS-CoV-2 in high-throughput live virus assays. Together, the proposed CAMPP is comprised of a collective team of scientists truly unmatched in non-profit drug discovery integrated with an industry-grade high-throughput screening facility with world-leading structural biologists, virologists and chemists to develop and apply innovative assays that recapitulate understudied aspects of the viral pathogenesis to identify and development new therapeutic antiviral approaches.