Gastrin-releasing peptide (GRP) is an evolutionarily well-conserved neuropeptide that was originally recognized for its ability to mediate gastric acid secretion in the gut. More recently, however, GRP has been implicated in pulmonary lung inflammatory diseases including bronchopulmonary dysplasia, chronic obstructive pulmonary disease, emphysema, and others. Antagonizing GRP or its receptor mitigated lethality associated with the onset of viral pneumonia in a well-characterized mouse model of influenza. In mice treated therapeutically with the small-molecule GRP inhibitor, NSC77427, increased survival was accompanied by decreased numbers of GRP-producing pulmonary neuroendocrine cells, improved lung histopathology, and suppressed cytokine gene expression. In addition, in vitro studies in macrophages indicate that GRP synergizes with the prototype TLR4 agonist, lipopolysaccharide, to induce cytokine gene expression. Thus, these findings reveal that GRP is a previously unidentified mediator of influenza-induced inflammatory disease that is a potentially novel target for therapeutic intervention.