Perforin is critical for cytotoxicity mediated by granules present in natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Perforin-deficient mice have impaired cytotoxicity by NK cells and CTLs, resulting in failure to control infections with certain viruses or bacteria. Infection of perforin-deficient mice with lymphocytic choriomeningitis virus results in haemophagocytic lymphohistiocytosis and elevated levels of pro-inflammatory cytokines. Mutations throughout the perforin gene have been identified in patients with familial haemophagocytic lymphohistiocytosis (FHL) type 2. These patients present with fever, hepatosplenomegaly, pancytopenia, have marked elevations of T-helper type 1 and type 2 cytokines, and have impaired NK cell and CTL cytotoxicity. A number of infectious pathogens have been implicated as triggering the onset of disease. Identification of mutations in perforin as the cause of FHL should allow prenatal diagnosis of the disorder. While stem cell transplantation is curative, gene therapy might be effective in the future.