Prone positioning is an immediately accessible, readily implementable intervention that was proposed initially as a method for improvement in gas exchange > 50 years ago. Initially implemented clinically as an empiric therapy for refractory hypoxemia, multiple clinical trials were performed on the use of prone positioning in various respiratory conditions, cumulating in the landmark Proning Severe ARDS Patients trial, which demonstrated mortality benefit in patients with severe ARDS. After this trial and the corresponding meta-analysis, expert consensus and societal guidelines recommended the use of prone positioning for the management of severe ARDS. The ongoing COVID-19 pandemic has brought prone positioning to the forefront of medicine, including widespread implementation of prone positioning in awake, spontaneously breathing, nonintubated patients with acute hypoxemic respiratory failure. Multiple clinical trials now have been performed to investigate the safety and effectiveness of prone positioning in these patients and have enhanced our understanding of the effects of the prone position in respiratory failure. In this review, we discuss the physiologic features, clinical outcome data, practical considerations, and lingering questions of prone positioning.