The mucosal surface of the digestive tract is a critical barrier between a broad spectrum of noxious and immunogenic substances present in the gastrointestinal lumen and the underlying mucosal immune system. Its preservation following various forms of injury or physiological damage is essential to prevent the invasion of harmful luminal factors into the host, which subsequently may lead to inflammation, uncontrolled immune response, and a disequilibrium of the homeostasis of the host. The preservation of this barrier following injuries is regulated by a broad spectrum of structurally distinct regulatory molecules, including phospholipids. Phospholipids play a pivotal role in the modulation of intestinal inflammation. They have been demonstrated to both promote and inhibit inflammation, and their overall impact in an individual setting seems to be dependent on several factors, including the level of immune cell activation and the presence of other mediators. Modulation of lipid mediators through administration of lysophosphatidic acid (LPA) or lisofylline (LSF), inhibitors of phospholipase A2 (PLA2) biosynthesis or monoclonal antibodies against thromboxane (TBX) or platelet-activating factor (PAF) as a therapeutic approach have been used in several models of inflammation; however, beneficial effects were not always convincing and further studies are warranted.