Arachidonic acid metabolites, the eicosanoids, are key mediators of allergen-induced airway inflammation and remodeling in asthma. The availability of free arachidonate in cells for subsequent eicosanoid biosynthesis is controlled by phospholipase A₂s (PLA₂s), most notably cytosolic PLA₂-α. 10 secreted PLA₂s (sPLA₂s) have also been identified, but their function in eicosanoid generation is poorly understood. We investigated the role of group X sPLA₂ (sPLA₂-X), the sPLA₂ with the highest in vitro cellular phospholipolysis activity, in acute and chronic mouse asthma models in vivo. The lungs of sPLA₂-X^−/− mice, compared with those of sPLA₂-X^+/+ littermates, had significant reduction in ovalbumin-induced infiltration by CD4⁺ and CD8⁺ T cells and eosinophils, goblet cell metaplasia, smooth muscle cell layer thickening, subepithelial fibrosis, and levels of T helper type 2 cell cytokines and eicosanoids. These data direct attention to sPLA₂-X as a novel therapeutic target for asthma.