Overt strokes occur in about 11% of children with sickle cell disease, and many more develop silent infarcts. Until recently, the only available management intervention was the use of chronic transfusions to prevent stroke recurrence. The stroke prevention trial in sickle cell anemia (STOP) demonstrated that children at risk for strokes can be identified by transcranial Doppler (TCD) ultrasonography. In high-risk patients, the risk of first stroke can be decreased by 90% if patients are placed on chronic transfusion regimens. However, transfusing all patients with abnormal TCD is also problematic; as many as 60% do not seem to develop a stroke. At this time, a more precise stratification of stroke risk based on imaging studies, genetic studies, and neuropsychological testing is needed. Moreover, the development of alternatives to chronic transfusions, such as hydroxyurea and other pharmacologic therapies, may also improve the outlook for patients at high risk for stroke.