Inhaled nitric oxide (iNO) has been used extensively to treat pulmonary hypertension primarily in newborns. This therapy is a safe and effective therapy to improve the matching between airway ventilation and blood oxygenation. A key conceptual component of iNO therapy is that effects are limited to the pulmonary compartment thereby avoiding unwanted systemic effects. The mechanism underlying this model is that any NO entering the blood stream is rapidly oxidized to nitrate, a relatively inert anion that is excreted. Mediating this oxidation is oxyhemoglobin that becomes oxidized to methemoglobin, accumulation of which is limited by erythrocyte methemoglobin reductase. In this article, we discuss studies that dismiss the notion that once in the blood stream iNO is inactivated and show that a surprising result of iNO therapy is the formation of stable NO-derived products that circulate and can elicit NO-dependent signaling in extra-pulmonary tissues. This pathway has the potential to open up new applications for iNO for treatment of systemic diseases associated with loss of NO signaling.