Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening and rare disease caused by a massive inflammatory response resulting in an uncontrolled cytokine storm. The primary form of HLH is typically seen in children and is most commonly a result of predisposing genetic mutations. Secondary or acquired HLH often lacks a genetic basis and typically occurs as a result of reactive immune activation due to an underlying infection, malignancy, autoimmune disorders, or following solid tumor or hematopoietic organ transplantation. Both primary and secondary forms of HLH carry a high mortality, especially if left untreated. Patients can present with pancytopenia, hepatosplenomegaly, fever, altered mentation, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, and multi-organ failure. Unfortunately, HLH can be easily masked or mistaken for sepsis or other inflammatory disease processes. Patients may not meet all diagnostic criteria at initial consideration of the diagnosis, but early treatment based on clinical suspicion is imperative. The mainstay of treatment for HLH is etoposide, a topoisomerase inhibitor, and steroids. Other agents such as tocilizumab, a humanized monoclonal antibody against IL6 receptors, and alemtuzumab, a CD52 antibody, have also been used as single agents or as part of a combination therapy. For the purpose of this chapter, we fill focus on secondary HLH caused by malignancy.