Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by uncontrolled hyperinflammation on the basis of various inherited or acquired immune deficiencies. Cardinal symptoms are prolonged fever, hepatosplenomegaly and cytopenias. Central nervous system (CNS) symptoms are common. Biochemical markers include elevated triglyceride and ferritin, high levels of the alpha chain of the soluble interleukin-2 receptor and low fibrinogen. Impaired function of natural killer (NK) cells and cytotoxic T-cells (CTL) is a characteristic of all forms of HLH. Genetic HLH occurs in familial forms (FHLH), in which HLH is the primary and only manifestation, and in association with the immune deficiencies Chédiak-Higashi syndrome (CHS), Griscelli syndrome (GS) and X-linked lymphoproliferative syndrome (XLP), in which secondary HLH occurs sporadically. Most patients with acquired HLH have no known underlying immune deficiency. Both acquired and genetic forms are triggered by infections, mostly viruses, or other stimuli. HLH also occurs as a complication of rheumatic diseases (macrophage activation syndrome) and of malignancies. The recent discovery of several genetic defects causing FHLH as well as the identification of the genes responsible for CHS, GS and XLP have underscored the role of granule (perforin/granzymes)-mediated cytotoxicity in both the killing of infected cells and the termination of the immune response. The immediate aim of therapy is suppression of the increased inflammatory response by immunosuppressive/immunomodulatory agents and cytotoxic drugs. Genetic cases can only be cured with stem cell transplantation. Awareness of the clinical symptoms and of diagnostic criteria for HLH is crucial to starting life-saving therapy in time.