Providing supplemental oxygen to hospitalized adults is a frequent practice and can be administered via a variety of devices. Oxygen therapy has evolved over the years, and clinicians should follow evidence-based practices to provide maximum benefit and avoid harm. This systematic review and subsequent clinical practice guidelines were developed to answer questions about oxygenation targets, monitoring, early initiation of high-flow oxygen (HFO), benefits of HFO compared to conventional oxygen therapy, and humidification of supplemental oxygen. Using a modification of the RAND/UCLA Appropriateness Method, 7 recommendations were developed to guide the delivery of supplemental oxygen to hospitalized adults: (1) aim for S pO 2 range of 94-98% for most hospitalized patients (88-92% for those with COPD), (2) the same S pO 2 range of 94-98% for critically ill patients, (3) promote early initiation of HFO, (4) consider HFO to avoid escalation to noninvasive ventilation, (5) consider HFO immediately postextubation to avoid re-intubation, (6) either HFO or conventional oxygen therapy may be used with patients who are immunocompromised, and (7) consider humidification for supplemental oxygen when flows > 4 L/min are used.