TWEAK (TNFSF12) is a "TNF-likeweak inducer" of apoptosis through a non-deathdomain-dependent mechanism. TWEAK is a type II membrane protein which exhibits a single internal hydrophobic domain of 27 amino acids in the N-terminal region. TWEAK is proteolytically cleaved to produce a soluble cytokine that signals as a trimerized molecule. Fibroblast growth factor-inducible 14 (Fn14)/TWEAKR has been described as a receptor for TWEAK, and it is associated with proliferation of endothelial cells and angiogenesis. However, TWEAK mediates signal transduction and linear differentiation of monocyte/macrophage cells lacking Fn14/TWEAKR, suggesting that such cells contain an alternative TWEAK receptor. Elevated levels of TWEAK and/or Fn14 have been found to be associated with the pathogenesis of rheumatoid arthritis, skeletal muscle wasting, systemic lupus erythematosus, multiple sclerosis, stroke, neuroinflammation and neurodegeneration, and several types of cancer. The pathological functions of TWEAK are primarily attributed to its ability to induce the expression of several proinflammatory cytokines, chemokines, cell adhesion molecules, and matrix-degradingenzymes mainly through the activation of NF-B, a major proinflammatorytranscription factor. More recently, it has been described that CD163 (a scavenger receptor) might be acting as a receptor "decoy" for the ligand TWEAK.