Although the manifestations of sickle cell disease (SCD) do not typically necessitate critical care management, several life-threatening complications may require admission to the pediatric intensive care unit. Children with SCD are at risk for serious complications such as vaso-occlusive pain crises, cerebral vascular accidents, acute chest syndrome, severe anemia related to aplastic and splenic sequestration crises, infection, and multiorgan failure. Despite years of study, little progress has been made in understanding the pathophysiology of SCD. For this reason, management has been primarily focused on treating the negative sequelae of the disease. However, exciting ongoing research has led to great improvements not only in the understanding of the disease, but also in what was once considered routine therapy for SCD. Research on the use of modalities such as inhaled nitric oxide, L-arginine therapy, and transcranial Doppler ultrasound, and the development of blood transfusion programs are making strides in reducing morbidity and mortality, and in improving the quality of life for children with SCD. Perhaps most exciting are the advances in bone marrow and stem cell transplantation, which offer hope of an eventual cure for this debilitating and deadly disease. Advanced practice nurses play a pivotal role in coordinating care for these critically ill children. Knowledge of both current and investigational therapies allows the advanced practice nurse to provide comprehensive, state-of-the-art care to children with life-threatening complications of SCD.