Multiple organ failure is a major threat to the survival of patients with sepsis and systemic inflammation. In the UK and in the USA, mortality rates are currently comparable with and projected to exceed those from myocardial infarction. The immune system combats microbial infections but, in severe sepsis, its untoward activity seems to contribute to organ dysfunction. In this Review we propose that an inappropriate activation and positioning of neutrophils within the microvasculature contributes to the pathological manifestations of multiple organ failure. We further suggest that targeting neutrophils and their interactions with blood vessel walls could be a worthwhile therapeutic strategy for sepsis.