As states and health systems prepare to deliver severe acute respiratory syndrome coronavirus 2 vaccines to the American public, a confluence of factors has the potential to interfere with these efforts: misinformation about coronavirus disease 2019, vaccine hesitancy, and the erosion of the American public's trust in the vaccine regulatory process due to recent and ongoing events. Broad action is needed to address these issues, including improved and consistent communication by the Food and Drug Administration, restoration of the Centers for Disease Control as an independent and science-driven institution, and more aggressive policies to counteract misinformation, particularly on social media platforms.