Oxidized phospholipids (OxPL) appear in the lung circulation as a result of increased oxidative stress that accompanies pathological conditions such as acute lung injury, lung inflammation, adult respiratory distress syndrome (ARDS), ventilator-induced lung injury (VILI), systemic inflammatory response syndrome (SIRS) and sepsis. Under these conditions, lung vascular barrier function is largely compromised. The severity of vascular endothelial dysfunction is determined by a balance between barrier-disruptive and barrier-protective agents present in the pulmonary circulation. Oxidation of phospholipids such as 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) generates a group of bioactive oxidized phospholipid species that demonstrate a wide spectrum of physiological effects including activation of monocyte adhesion to endothelial cells and attenuation of inflammatory cascades triggered by bacterial lipopolysaccharide (LPS). Moreover, our studies and other previous reports strongly suggest barrier-protective effects of OxPAPC on human pulmonary EC, and EC from systemic circulation. In this review, we will discuss a potential role for biologically active oxidized phospholipids in the regulation of vascular barrier integrity and LPS-induced inflammation in the injured lung.