Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by excessive activation of the immune system, resulting in overproduction of inflammatory cytokines. Patients usually present with high fever, cytopenias, hyperferritinemia, and hepatosplenomegaly, and their disease process ranges from mild to fatal multiorgan failure. HLH is a heterogeneous group of disorders that can be triggered by infections, neoplasms, or autoimmune diseases. The HLH diagnosis can be difficult to confidently confirm in critically ill patients while waiting for pathology or reference laboratory results to return, delaying the diagnosis with significantly worsened outcomes. The current HLH-2004 diagnostic guidelines were originally developed for pediatric cases and were not validated to diagnose secondary HLH, whether in children or adults. In addition, some laboratory findings that are common among HLH patients such as hypoalbuminemia and elevated liver enzymes are not represented in the HLH-2004 guidelines. Even more challenging for clinicians is that many of the diagnostic features of this syndrome are nonspecific. For example, the clinical presentation of HLH can meet the diagnostic criteria of systemic inflammatory response syndrome, viral infections, or neoplastic diseases. It is necessary to revisit the diagnostic criteria for HLH by validating the clinical and laboratory findings in large prospective HLH prospective clinical trials or by establishing registries. This will improve our understanding of HLH, help validate and develop newer, more specific, and more rapidly obtainable diagnostic criteria, and, eventually, result in earlier therapy with more consistent monitoring of the response.