 Stroke occurs in 10 of Sickle Cell Disease SCD patients before the age of 20 Years. Current standard of care for secondary overt stroke prevention in patients with SCD is chronic red blood cell RBC transfusions. Stroke recurs in 60 of patients without chronic RBC therapy and in 20 of patients with chronic transfusion while maintaining a hemoglobin S percentage of less than 30. Indefinite transfusion therapy is practiced as discontinuation after short-term or long-term prophylactic transfusions leads to recurrent overt strokes and more ensuing CNS damage, even with transition to hydroxyurea. Chronic transfusions also prevent initial stroke in high-risk patients identified by transcranial Doppler TCD ultrasound. The Stroke Prevention Study in Sickle Cell Disease STOP demonstrated a 92 stroke risk reduction among 63 of 130 children with abnormal TCD results. Rates of stroke declined significantly since implementing routine TCD screening and primary prophylactic transfusion therapy. The subsequent STOP 2 trial supports the use of chronic transfusion indefinitely because discontinuation resulted in an increased rate of abnormal TCD conversion and development of overt stroke. Discontinuing transfusions on the STOP 2 trial was also associated with a higher occurrence of silent cerebral infarcts, documented in 3 of 37 patients 8.1 in the continued-transfusion group compared with 11 of 40 27.5 in the transfusion-halted group. More recent studies demonstrate that SCD patients are also at risk for silent cerebral infarcts. An association between worsening vasculopathy shown by magnetic resonance angiography and progressive overt and silent infarcts on magnetic resonance imaging has been found. More aggressive magnetic resonance imaging screening may be indicated and this could result in more patients with SCD treated with chronic transfusion. 