Persons with sickle cell disease (SCD) are more likely to undergo surgery than are the general population during their lifetime. For example, cholecystectomy as a consequence of gallstones is more frequent in persons with SCD, as is hip arthroplasty in younger people as a result of avascular necrosis of the femoral head. Because surgery exposes patients to many of the factors that are known to precipitate red blood cell sickling, persons with SCD undergoing surgery require meticulous clinical care to prevent perioperative sickle cell–related complications. Even with meticulous care, approximately 25% to 30% of patients will have a postoperative complication. This article provides readers with information about the role of surgery in SCD and the measures that should be taken to ensure patients are well cared for in the perioperative period.