Recent progress has been made in discovering structure/function relationships of the cytotoxic lymphocyte pore-forming protein — perforin — and its role in immune regulation. Long recognized as a key component of the granule exocytosis mechanism of lymphocyte-mediated apoptosis and in host defence against a variety of pathogens and tumors, more recent attention has focused upon mutations of the perforin gene in some patients with hemophagocytic lymphohistiocytosis. This clinical picture has prompted further work to uncover the molecular structure of perforin and to define its precise role in immune regulation and immunopathology.