Hemophagocytic lymphohistiocytosis represents a spectrum of pathogenetically different diseases including the rapidly fatal autosomal recessive disease of familial hemophagocytic lymphohistiocytosis (FHL). The onset is usually during the first years of life with fever, cytopenia, and hepatosplenomegaly. Neurologic symptoms may supervene. Similar symptoms may occur in the infection-(virus-)associated or malignancy-associated hemophagocytic syndromes (IAHS/MAHS). Triggering infections can be found in all these diseases and do not allow for reliable differentiation. An international treatment protocol (HLH-94) has been developed for FHL, but immunomodulatory treatment may be justified in IAHS and MAHS as well, since they also have a high fatality rate.