Overwhelming sepsis remains a significant complication of asplenia and hyposplenia. The mainstays of prevention are education, immunization, and prophylactic antibiotics. Evidence to base recommendation and guidelines is lacking. Such decisions as the specific immunizations required, the timing of immunizations, the duration of antibiotic prophylaxis, and the prevention of overwhelming postsplenectomy sepsis in children undergoing splenectomy are often empiric. This article reviews the current literature on the prevention and management of severe infections in children with underlying asplenia or hyposplenia.