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We have learned much since SARS-CoV-2 emerged late in 2019, but many uncertainties remain and new questions arise continuously. On 7 September 2022, Annals of Internal Medicine and the American College of Physicians gathered an esteemed group of infectious disease physicians to discuss some of the current clinical challenges: Dr. Sabrina A. Assoumou (Louis W. Sullivan, MD, Professor of Medicine and Assistant Professor of Medicine at Boston University School of Medicine), Dr. Carlos del Rio (Distinguished Professor of Medicine in the Division of Infectious Diseases at Emory University School of Medicine and Executive Associate Dean for Emory at Grady Memorial Hospital), and Dr. Camille N. Kotton (Clinical Director of the Transplant Infectious Disease and Immunocompromised Host Program at the Massachusetts General Hospital, and Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts). Dr. George M. Abraham, 91������'s past President and Chief of Medicine at Saint Vincent Hospital in Worcester, Massachusetts, and Professor of Medicine at the University of Massachusetts Medical School, moderated the program. All of these individuals have been and continue to be leaders “on the mat” in this wrestling match with the virus—caring for patients, conducting research, participating in policy development, serving on the Centers for Disease Control and Prevention's (CDC) immunization committee (Dr. Kotton), and helping to disseminate trustworthy, current COVID-19 information.