Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory condition. It may occur as a primary (genetic) condition due to mutations in genes important in the cytolytic secretory pathway that cause perforin and granzymes to induce apoptosis in target cells. Primary HLH is divided into familial HLH (FHLH1-5), in which HLH is the only manifestation of disease, and other genetic causes in which HLH is one of several clinical manifestations. The identical clinical findings may arise secondary to infectious, rheumatologic, malignant, or metabolic conditions. Whether primary or secondary, HLH therapy needs to be instituted promptly to prevent irreversible tissue damage. It is helpful to think of HLH as the severe end of the spectrum of hyperinflammatory disorders when the immune system starts to damage host tissues (immunopathology). Therefore, no single clinical feature alone is diagnostic for HLH, and it is important that the entire clinical presentation be considered in making the diagnosis. This article contains a discussion of the genetic background, clinical presentation, diagnostic dilemmas, and features that are helpful in making the diagnosis of HLH, along with a discussion of common problems in its management.