Patients with sickle cell disease frequently require red blood cell transfusions. However, transfusions can cause delayed hemolytic transfusion reaction (DHTR), a serious and potentially life-threatening complication of alloimmunization that results in hemolysis of transfused as well as patients' own red cells. Although we are beginning to understand some of the pathophysiology and risk factors associated with alloimmunization, optimal management of DHTR in this patient population is still under debate. Here, I will review the clinical features, pathophysiology, laboratory evaluation, current strategies for management and prevention of DHTRs. Given that DHTRs are associated with massive hemolysis, it is recommended that all patients with sickle cell disease receiving transfusions are carefully and systematically monitored after each transfusion.