Children with sickle cell disease are at risk of developing neurologic complications, including stroke, transient ischemic attack, seizures, coma, and a progressive reduction in cognitive function. Transcranial Doppler ultrasound, magnetic resonance imaging, and overnight pulse oximetry appear to predict, making prevention an achievable goal so that there is now a focus on randomized controlled trials. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) reported a reduction in the number of overt clinical strokes experienced by those children with critically high transcranial Doppler velocities (>200 centimeters per second) who were chronically transfused. Two additional Phase III studies and two pilot trials have been funded. STOP II focused on whether it is safe to discontinue blood in prophylactically transfused children when their velocities had remained normal for at least 30 months. The Silent Infarct Transfusion trial is designed to determine whether children with sickle cell anemia and silent cerebral infarcts, approximately 20% of the population, will have a decrease in the progressive neurologic complications after receiving regular blood transfusion therapy. Pilot safety and feasibility trials of low-dose aspirin and overnight respiratory support are also beginning. The collaboration provides an infrastructure for future clinical trials in this vulnerable group of children.