The American College of Physicians (ACP) and the Centers for Disease Control and Prevention (CDC) recently published advice for high-value care on the appropriate use of antibiotics for acute respiratory tract infections. They conducted a narrative literature review of evidence for antibiotic use in this setting that included recent clinical guidelines from professional societies supplemented by randomized, controlled trials; meta-analyses; and systematic reviews. They concluded that clinicians should reserve antibiotic treatment for acute rhinosinusitis in patients with persistent symptoms for more than 10 days, high fever and purulent nasal discharge or facial pain lasting for at least 3 consecutive days, or worsening symptoms after a typical viral illness that lasted 5 days and had initially improved (“double-sickening”). In this Grand Rounds, 2 prominent clinicians debate whether to initiate antibiotic treatment in a 62-year-old man with a history of recurrent sinusitis who presents with persistent upper respiratory symptoms. They review the data on which the ACP/CDC recommendations are based and discuss the potential benefits and risks, as well as the challenges and controversies, of prescribing antibiotic therapy in this setting.