Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory disorder characterized by activation and proliferation of lymphocytes and histiocytes with cytokine release and uncontrolled hemophagocytosis, especially late in the course of the disease. Clinical features include relapsing fevers, hepatosplenomegaly, cytopenias, lymphadenopathy, and coagulopathy. The diagnosis can be challenging, as the early signs and symptoms are nonspecific and no specific laboratory tests exist. This syndrome is frequently not recognized and has a significant mortality rate. Typical scenarios in which HLH should be considered include mononucleosis (fever, hepatosplenomegaly, and lymphadenopathy) in an infant or young child, aseptic meningitis associated with cytopenias, or a viral syndrome-like illness with cytopenias and lymphadenopathy or splenomegaly, for example. Our approach includes measuring a ferritin level as a screening tool early in the course of such an illness. Two cases of HLH are reviewed, illustrating the frequent complexity of these cases and potential pitfalls to making a prompt diagnosis.