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On January 19, 2020, the first case of a patient with coronavirus disease 2019 (COVID-19) in the United States was reported in Washington State. On February 29, 2020, a patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) passed away in a hospital in Seattle-King County, the first reported COVID-19-related death in the United States. That same day, a skilled nursing and rehabilitation facility in the county reported that several of its residents tested positive for SARS-CoV-2 and that many staff had symptoms compatible with COVID-19. The University of Washington Medicine health system (UW Medicine), which is based in Seattle-King County and provides quaternary care for the region, was one of several health care organizations called upon to address this growing crisis. What ensued was a series of swiftly enacted decisions and activities at UW Medicine, in partnership with local, state, and national public health agencies, to respond to the COVID-19 pandemic. Tapping into the multipronged mission areas of academic medicine, UW Medicine worked to support the community, innovate in science and clinical practice; lead policy and practice guideline development; and adopt changes as the crisis unfolded. In doing so, health system leaders had to balance their commitments to students, residents and fellows, researchers, faculty, staff, and hospital and health center entities, while ensuring that patients continued to receive cutting-edge, high-quality, safe care. In this Invited Commentary, the authors highlight the work and challenges UW Medicine has faced in responding to the global COVID-19 pandemic.