Atherosclerosis is currently described as an inflammatory disease given that the main components of chronic inflammation are present in this process: cell recruitment, proliferation, neovascularization, and sclerosis. Vascular lesions are caused by inflammatory and fibroproliferative responses to injury of the endothelium and vascular smooth muscle cells. Interaction between members of the tumor necrosis factor (TNF) superfamily and their receptors elicits diverse biologic actions that participate in atherosclerosis development. These responses include the expression of adhesion molecules, proinflammatory cytokines, matrix metalloproteinases, and tissue factor, which are known to increase plaque instability. TNF-like weak inducer of apoptosis (TWEAK) is a recently described member of the TNF superfamiliy, which is involved in induction of inflammation, activation of cell growth, and stimulation of apoptosis. In this review, we summarize the potential proatherogenic consequences of the interaction of TWEAK with its receptor Fn14 in the vascular wall.