Sickle cell disease is the most common inherited disease in African Americans, affecting at least 50,000 individuals. At present, there is no cure. Despite improvement in survival, median life expectancy remains 42 years for males and 48 years for females. There is an increasing appreciation of both the acute and chronic pulmonary manifestations of sickle cell disease and their role in the morbidity and mortality of this disease. Acute manifestations include the acute chest syndrome, pulmonary thromboembolism, and episodic respiratory symptoms that suggest an asthma-phenotype. Chronic manifestations include abnormal pulmonary function, hypoxemia, evolving pulmonary hypertension, and exercise intolerance. Sickle chronic lung disease is a clinical continuum characterized by dyspnea, exercise intolerance, pleuritic chest pain, and progressive deterioration in pulmonary function. Timely cardiopulmonary assessment in both the acute and chronic setting provides ample opportunity for effective intervention. Recent insights into the pulmonary pathophysiology of sickle cell disease suggest ongoing lung injury may be related to ischemia/reperfusion, pulmonary vasculopathy, and alterations in nitric oxide metabolism. These insights offer the potential for novel therapies and management strategies that may alter the natural history of sickle cell disease.