Recent studies have demonstrated that extracellular histones, either free or associated with 'neutrophil extracellular traps' (NETs), although playing an anti-microbial role can also cause catastrophic immunopathology. This is due to the histones and NETs being cytotoxic, inducing coagulation and damaging erythrocytes. In fact, NETs are now thought to be the major initiator of sepsis. We have recently developed small, polyanionic, molecules that neutralise the damaging effects of histones and NETs and can very effectively protect experimental animals from septic shock. Current studies are validating a lead compound for clinical use.