Acute respiratory distress syndrome (ARDS) is characterized by perfusion in favor of non-ventilated areas of the lungs as the main cause of intrapulmonary right-to-left shunt and hypoxemia. Therapeutic interventions to selectively influence pulmonary perfusion in ARDS became possible with the introduction of inhaled nitric oxide (iNO), which provided a way not only to reduce pulmonary hypertension, but also to acutely improve ventilation-perfusion mismatch, and thus to treat severe hypoxemia. Clinical studies in ARDS demonstrated that the combination of iNO with other interventions, such as positive end-expiratory pressure (PEEP) and prone positioning, yielded beneficial and additive effects on arterial oxygenation. Although randomized controlled trials of this concept have up to now failed to show an improved outcome, iNO is a valuable option for the treatment of severe refractory hypoxemia in ARDS patients.