Hemophagocytic lymphohistiocytosis (HLH) is a primary immune system disorder that results from defective cell-to-cell signaling and disruption of inflammatory system homeostasis (Zhang K, Jordan MB, Marsh RA et al. Blood 118(22):5794–5798, 2011). There are two major types of HLH: primary HLH, which arises from genetic mutations and occurs almost exclusively in children, and secondary HLH, which arises from an external trigger like infection or malignancy, and is seen in both children and adults (Schram AM, Berliner N. Blood 125(19):2908–2914, 2015). In both cases, HLH usually is initiated by an external stimulus. Epstein–Barr virus (EBV) is one of the more frequently implicated infections in the pathogenesis of HLH, but many other infections have also been associated with the syndrome (George MR. J Blood Med 5:69–86, 2014). Several inherited gene mutations have been demonstrated to cause primary HLH, all of which occur in genes that affect homeostasis of the inflammatory response (Cetica V, Sieni E, Pende D et al. J Allergy Clin Immunol 137(1):188–196.e184, 2016). Without such a regulatory system, cytokines and other inflammatory mediators are produced unchecked, resulting in fever, multiple organ system failure, pancytopenia, and death in many patients if treatment is not initiated promptly (Schram AM, Berliner N. Blood 125(19):2908–2914, 2015). Recognition of this rare disorder continues to increase as improved diagnostic tools become available to medical centers worldwide. Improved recognition and research of this condition have led to the potential for significant improvement in the diagnosis and treatment of patients with HLH.