Hemophagocytic lymphohistiocytosis (HLH) is a prototype of the hemophagocytic syndrome and occurs most often in children. Progress in cytokine research has now made it possible to show that HLH occurs as a consequence of uncontrolled, dysregulated cellular immune reactivity caused by a number of different underlying diseases. Three major risk groups of HLH can be identified: (1) familial HLH (FHL), (2) Epstein-Barr virus-associated HLH (EBV-HLH), and (3) life-threatening infection-associated or underlying disease-unknown HLH in infancy. Diagnostic criteria now exist that allow the differential diagnosis of these groups, which is important because distinct therapeutic measures are advised for each group. FHL patients require immediate application of immunochemotherapy with a core combination of corticosteroids and etoposide together with monitoring of central nervous system disease by early and repeated magnetic resonance imaging of the brain, followed by timely stem cell transplantation (SCT). EBV-HLH should also be treated with a combination of corticosteroids and etoposide. Aggressive or relapsed cases should be treated with cyclosporin A and, if necessary, with more intensive chemotherapy, such as that used for non-Hodgkin's lymphoma. SCT may also be needed in these refractory cases. In cases of herpes simplex virus, adenovirus 7, and other pathogen-undetermined HLH in early infancy, it is of great importance to administer appropriate antiviral or antibacterial agents. The most important point to make regarding HLH treatment is that the underlying cause of HLH must be promptly established to enable the rapid application of the appropriate therapy. Currently, 30% to 40% of HLH cases have a poor outcome. It is necessary for hematologists to cooperate with specialists in other fields so that early diagnosis, which is critical for improvements in outcome, can be made.