Sickle cell disease is associated with a high risk of stroke in the early years of childhood. The risk of a secondary stroke can be significantly reduced through chronic blood transfusions. Prevention of the first stroke (primary prevention) was made possible through the use of transcranial Doppler (TCD) US and demonstrated in a randomized clinical trial called the stroke prevention trial in sickle cell anemia (STOP). TCD results were classified as normal, conditional, abnormal or inadequate based on velocity readings in specific arterial segments. The MCA and ICA were carefully searched to find the highest velocity, and this was used to stratify patients as to stroke risk. Those with abnormal or high-risk TCD received either monthly blood transfusions or no transfusions, and those randomized to transfusion had a much better outcome in terms of stroke (one stroke, versus ten in the control group) and also fewer other medical problems while transfused. TCD screening is recommended for SCD patients to begin at 24 months of age and should be repeated every 6-12 months during early childhood. Transcranial Doppler imaging (TCDI) can be easier to use and learn and with a few adjustments can provide equivalent predictive power. Currently, TCD is the only recommended method for treatment selection for primary-stroke prevention. MRI and MRA can provide important information on the status of the brain and the blood vessels and, when abnormal, indicate greater risk. Although TCD cannot predict all strokes, TCD and TCDI offer an opportunity to apply an effective therapy for patients in this risk group and reduce many first-time strokes.