The spleen contributes importantly to the normal and pathologic removal of blood cells from the circulation and to defense against infection with encapsulated bacteria. Surgical splenectomy provides efficacious treatment for a number of pediatric disorders but is associated with perioperative morbidity and a life-long risk of overwhelming infection. Alternatives to conventional splenectomy include laparoscopic splenectomy, partial splenectomy, partial splenic embolization, and autologous splenic transplantation. Sickle cell disease is the most common cause of functional asplenia in children. Asplenia develops during infancy in many infants with sickle cell anemia, and prophylactic penicillin markedly reduces mortality from pneumococcal infection. In contrast, recent evidence suggests that children with sickle-hemoglobin C disease do not develop functional asplenia before 3 to 4 years of age and thus may not benefit from penicillin prophylaxis. Recommendations for the treatment of asplenic patients include pneumococcal, Haemophilus influenzae type b, and meningococcal immunizations, antimicrobial prophylaxis for selected patients, and prompt evaluation and aggressive treatment of acute febrile illness.