Extracellular histones are identified as major mediators of death in sepsis, contributing to endothelial dysfunction, organ failure, and mortality. These histones can be targeted pharmacologically by antibodies or activated protein C (APC). Antibody to histone reduced mortality in models of sepsis, while APC cleaves histones, reducing their cytotoxicity. In vivo studies in baboons and mice showed that histone administration led to neutrophil margination, vacuolated endothelium, intra-alveolar hemorrhage, and thrombosis. APC co-infusion prevented lethality, and blocking protein C activation exacerbated sublethal sepsis. The study concludes that extracellular histones are potential therapeutic targets for sepsis and other inflammatory diseases.Extracellular histones are identified as major mediators of death in sepsis, contributing to endothelial dysfunction, organ failure, and mortality. These histones can be targeted pharmacologically by antibodies or activated protein C (APC). Antibody to histone reduced mortality in models of sepsis, while APC cleaves histones, reducing their cytotoxicity. In vivo studies in baboons and mice showed that histone administration led to neutrophil margination, vacuolated endothelium, intra-alveolar hemorrhage, and thrombosis. APC co-infusion prevented lethality, and blocking protein C activation exacerbated sublethal sepsis. The study concludes that extracellular histones are potential therapeutic targets for sepsis and other inflammatory diseases.