Lung injury is marked by a persistent self‐propagating inflammation within the pulmonary tissue that is initiated by the migration of leukocytes into the alveolar space. Recent work has demonstrated that neuronal guidance proteins are involved into the orchestration of leukocyte migration. Neogenin is a crucial guidance receptor for axonal migration, yet its role during leukocyte migration and acute inflammation is to date unknown. Here, we report that neogenin influences neutrophil migration across endothelial HMEC‐1 and alveolar A549 monolayers in vitro. In vivo, Neo1^‐/‐ mice demonstrated 59% reduced cell count, 41% reduced TNF‐α, and 76% reduced IL‐6 levels within the alveolar space during lung injury. In studies employing chimeric animals, the presence of Neo1^‐/ bone marrow was associated with a 42% reduction of cell count and reduced inflammatory changes within pulmonary tissue during lung injury. The functional inhibition of neogenin through antibody injection confirmed these results and the role of neogenin for the inflammatory changes within the alveolar space. Previously unappreciated, the guidance receptor neogenin has a significant effect on the orchestration of leukocyte migration and the control of acute inflammation.—Mirakaj, V., Jennewein, C., König, K., Granja, T., Rosenberger, P. The guidance receptor neogenin promotes pulmonary inflammation during lung injury. FASEB J. 26, 1549‐1558 (2012). www.fasebj.org