SummaryHuman and murine neutrophils differ with respect to representation in blood, receptors, nuclear morphology, signaling pathways, granule proteins, NADPH oxidase regulation, magnitude of oxidant and hypochlorous acid production, and their repertoire of secreted molecules. These differences often matter and can undermine extrapolations from murine studies to clinical care, as illustrated by several failed therapeutic interventions based on mouse models. Likewise, coevolution of host and pathogen undercuts fidelity of murine models of neutrophil‐predominant human infections. However, murine systems that accurately model the human condition can yield insights into human biology difficult to obtain otherwise. The challenge for investigators who employ murine systems is to distinguish models from pretenders and to know when the mouse provides biologically accurate insights. Testing with human neutrophils observations made in murine systems would provide a safeguard but is not always possible. At a minimum, studies that use exclusively murine neutrophils should have accurate titles supported by data and restrict conclusions to murine neutrophils and not encompass all neutrophils. For now, the integration of evidence from studies of neutrophil biology performed using valid murine models coupled with testing in vitro of human neutrophils combines the best of both approaches to elucidate the mysteries of human neutrophil biology.