Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are potent bioactive phospholipids with specific and multiple effects on blood cells and cells of the vessel wall. Released by activated platelets, LPA and S1P mediate physiological wound healing processes such as vascular repair. Evidence is accumulating that these lipid mediators can, however, under certain conditions become athero- and thrombogenic molecules that might aggravate cardiovascular disease. For example, LPA present in minimally modified LDL and within the intima of atherosclerotic lesions may play a role in the early phase of atherosclerosis by inducing barrier dysfunction and increased monocyte adhesion of the endothelium, as well as in the late phase by triggering platelet activation and intra-arterial thrombus formation upon rupture of the atherosclerotic plaque. Moreover, LPA and S1P, by stimulating the proliferation of fibroblasts and by enhancing the survival of inflammatory cells are likely to play a central role in the excessive fibroproliferative and inflammatory response to vascular injury that characterizes the progression of atherosclerosis. Furthermore, LPA can cause the phenotypic dedifferentiation of medial vascular smooth muscle cells, and S1P is able to stimulate the migration and proliferation of intimal vascular smooth muscle cells; both processes ultimately lead to the formation of the neointima. Most importantly, as LPA and S1P bind to and activate multiple G-protein receptors, it emerges that the beneficial or harmful action of LPA and S1P are critically dependent on the expression profile of their receptor subtypes and their coupling to different signal transduction pathways in the target cells. By targeting specific subtypes of LPA and S1P receptors in selective cells of the vascular wall and blood, new strategies for the prevention and therapy of cardiovascular diseases can be envisioned.