Calcium influx is important for several neutrophil effector functions, but the effects of altered calcium signalling have not been investigated in neutrophils in vivo. Now, Zhang et al. show that the calcium-sensing molecule stromal interaction molecule 1 (STIM1) is important for neutrophil-mediated killing of bacteria. Mouse neutrophils that lacked Stim1 showed a loss of store-operated Ca2+ entry (SOCE), which mediates a sustained increase in cytosolic Ca2+ concentration. Mice that lacked Stim1 were more susceptible to infection with Listeria monocytogenes and Staphylococcus aureus than wild-type mice owing to diminished neutrophil superoxide production. These mice also showed increased protection from tissue damage in a model of hepatic ischaemia and reperfusion injury. The authors speculate that blockade of SOCE in neutrophils could provide a novel approach to treat inflammation-induced tissue damage.