Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of structurally-related cytokines. TWEAK acts on responsive cells via binding to a cell surface receptor named fibroblast growth factor-inducible 14 (Fn14). TWEAK can regulate numerous cellular responses in vitro including cell proliferation, migration, survival, differentiation and apoptosis. TWEAK is also a proangiogenic and proinflammatory factor in vivo. Recent studies have indicated that pharmacological inhibition of TWEAK activity may have therapeutic efficacy in several diseases including ischemic stroke, cerebral edema, multiple sclerosis and rheumatoid arthritis. In this review we first introduce the TWEAK-Fn14 signaling system and then focus on the potential therapeutic utility of soluble Fn14-Fc fusion proteins and TWEAK neutralizing antibodies.