Stroke is a significant cause of morbidity and mortality in children and adults with sickle cell disease. Great advances in the past couple of decades have enabled identification and treatment of children at risk of stroke, with a resultant dramatic reduction in stroke incidence in children. However, prevention and treatment of silent cerebral infarcts remain a challenge. This article reviews our current understanding of the epidemiology, risk factors and pathophysiology of small and large vessel disease with a focus on pediatric patients. The presentation and acute management of stroke in patients with sickle cell disease are discussed. Current recommendations for primary and secondary stroke prevention, as well as ongoing research studies and potential new therapies are reviewed.