This chapter discusses the diagnosis, evaluation and management of sickle cell emergencies. Patients with sickle cell disease (SCD) are functionally asplenic after early childhood and are in a persistent immunocompromised state, placing them at increased risk for serious infections from encapsulated organisms. Common infections associated with SCD include pneumonia (from Streptococcus pneumoniae, Haemophilus influenzae, and Mycoplasma pneumoniae), meningitis, and osteomyelitis (from Salmonella typhimurium, Staphylococcus aureus, and Escherichia coli). Acute chest syndrome (ACS) is the leading cause of death in patients with SCD. Splenic sequestration, or intrasplenic trapping of red blood cells (RBCs), is a major cause of morbidity and mortality in SCD. It is more common in children who have not yet undergone splenic auto-infarction. Patients can rapidly deteriorate and develop altered mental status, hypotension, and cardiovascular collapse secondary to anemia and hypovolemic shock. The condition can be fatal within hours.