Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are conditions associated with an estimated mortality of 40–50%. The use of inhaled vasodilators can help to improve oxygenation without hemodynamic effects. This article reviews relevant studies addressing the safety and efficacy of inhaled nitric oxide (iNO) and aerosolized epoprostenol (aEPO) in the treatment of life-threatening hypoxemia associated with ARDS and ALI. In addition, the article also provides a practicable guide to the clinical application of these therapies. Nine prospective randomized controlled trials were included for iNO reporting on changes in oxygenation or clinical outcomes. Seven reports of aEPO were examined for changes in oxygenation. Based on currently available data, the use of either iNO or aEPO is safe to use in patients with ALI or ARDS to transiently improve oxygenation. No differences have been observed in survival, ventilator-free days, or attenuation in disease severity. Further studies with consistent end points using standard delivery devices and standard modes of mechanical ventilation are needed to determine the overall benefit with iNO or aEPO.