Sickle cell anemia is one of the most prevalent genetic diseases worldwide. Pulmonary disease, manifested as the acute chest syndrome (ACS), is a common complication of sickle cell anemia, accounting for 25% of premature deaths (1). The last decade has witnessed a convergence of research pathways that are leading toward a better understanding of ACS pathophysiology and possible new therapies. A fascinating picture is emerging from one of these pathways, the study of nitric oxide (NO) biology, suggesting that hemoglobin binds NO and regulates local pulmonary NO concentration and delivery of NO to the microvascular system. This mechanism raises the possibility of new therapies for sickle cell anemia based on NO. This pulmonary perspective will summarize the current understanding of the pathogenesis and clinical characteristics of sickle cell anemia and the acute chest syndrome. New data on the effects of NO on sickle cell hemoglobin (hemoglobin S) and the microvasculature will be detailed. In addition, a description of the interactions of NO with hemoglobin to regulate hypoxic pulmonary vasoconstriction and ventilation perfusion matching will be presented. In conclusion, this discussion will provide conjecture on the putative role of NO and hemoglobin in the pathogenesis of sickle cell anemia and the acute chest syndrome and its therapeutic implications.