Acute chest syndrome (ACS) is the presence of a new pulmonary infiltrate in combination with fever or respiratory symptoms in a patient with sickle cell disease. ACS is the leading cause of death in sickle cell disease, and many patients suffer from multiple, severe episodes. Age has a striking effect on the clinical course and outcome of ACS, with children having milder disease that often is infectious. Adults often have severe disease, and pulmonary fat embolism is frequently a component of severe ACS. Rapid diagnosis and appropriate therapy including antibiotics for atypical infections, fluids, aerosolized beta agonists, and adequate pain control are necessary to reduce morbidity. Transfusion is indicated in hypoxic patients and can be used to prevent recurrent episodes. As the pathophysiology of ACS is further delineated, new treatment strategies will be investigated.