Administration of inhaled nitric oxide (NO) with the existing compressed gas delivery systems is associated with unavoidable codelivery of nitrogen dioxide (NO2), an unwanted toxic contaminant that forms when mixed with oxygen. The NO2 is generated when NO is diluted with O2-enriched air before delivery to the patient. When NO2 is inhaled by the patient, it oxidizes protective antioxidants within the epithelial lining fluid (ELF) and triggers extracellular damage in the airways. The reaction of NO2 within the ELF triggers oxidative stress (OS), possibly leading to edema, bronchoconstriction, and a reduced forced expiratory volume in 1 second. Nitrogen dioxide has been shown to have deleterious effects on the airways of high-risk patients including neonates, patients with respiratory and heart failure, and the elderly. Minimizing co-delivery of NO2 for the next generation delivery systems will be a necessity to fully optimize the pulmonary perfusion of NO because of vasodilation, whereas minimizing the negative ventilatory and histopathological effects of NO2 exposure during inhaled NO therapy.