Overt strokes, previously one of the most common neurological complications in sickle cell disease (SCD), have become far less frequent with routine transcranial Doppler (TCD) assessment followed by regular blood transfusion therapy. Nevertheless, children and adults with SCD continue to have overt strokes, and in the foreseeable future will continue to require secondary prevention of strokes. With the exception of the most recently completed "Stroke With Transfusions Changing to Hydroxyurea" Trial (SWiTCH; NCT00122980), randomized trials providing best evidence for long-term management of overt strokes in SCD is lacking. Instead of randomized clinical trials, a series of observational and single-arm studies have predominated. This review assesses the best available evidence for acute and chronic management of overt stroke and the efficacy of regular blood transfusion therapy, hydroxyurea therapy, and hematopoietic stem cell transplantation (HSCT), including matched sibling donor and unrelated HSCT.