Cardiovascular diseases are the leading cause of mortality in the Western world. The underlying pathological process is a thickening of the arterial wall due to the formation of atheromatous plaques which contain a lipid core covered by a fibrous cap. The main mechanisms involved in atherogenesis are: lipoprotein retention, endothelial cell activation, vascular smooth muscle cell proliferation, macrophage infiltration, proteolytic injury, neovascularization and apoptosis. Different members of the tumor necrosis factor family (TNF) of proteins have been detected in human atherosclerotic plaques, among these are TNF-related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-Rs and osteoprotegerin, OPG). In this review, the involvement of TRAIL and its receptors in the mechanisms underlying atherothrombosis is reviewed. In this respect, there are still some controversial data on the effects of TRAIL on inflammation and apoptosis of vascular cells. However, recent in vivo studies have suggested a potential proinflammatory and proapoptotic role of TRAIL in vascular injury. In addition, soluble forms of the TNF-superfamily can be released extracellularly and have been detected in human plasma. For this reason, we different studies evaluating the potential use of TRAIL and OPG plasma levels as markers of vascular injury are discussed.