Sickle cell disease affects many organ systems, but one of the major morbidities is brain disease, especially stroke. In this paper, the etiology, diagnosis, treatment, and prevention of clinical stroke, as well as so-called "silent stroke," are examined. Risk factors, diagnostic tools, and data from prevention and treatment studies as well as issues pertaining to neuropsychological function, especially in younger patients, are discussed and current best options for treatment considered.