Perforin defects have been identified in humans with familial hematophagocytic lymphohistiocytosis. The pathology of these patients has dramatically illustrated an under-appreciated role for perforin in the regulation of T-cell responses in vivo, and experimental studies are shedding light on the mechanisms involved. The detailed molecular mechanisms of perforin's mandatory role in the cytotoxic T lymphocyte (CTL)-mediated granule exocytosis death pathway and of granzyme entry into target cells remain unclear. In model systems measuring apoptosis by granzyme B and sublytic perforin, pore formation is undetectable during granzyme entry. Selfprotection of cytotoxic lymphocytes after degranulation can be explained by surface expression of the granule protease cathepsin B, as shown by suicidal degranulation in the presence of specific inhibitors.