Tumor necrosis factor (TNF)-Iike weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily of structurally related cytokines and is known to induce proliferation, migration, differentiation, apoptotic celt death, inflammation, and angiogenesis. These physiological processes are induced by the binding of TWEAK to fibroblast growth factor-inducible 14 (Fn14), a highly inducible cell-surface receptor that is linked to several intracellular signaling pathways, including the nuclear factor-KB (NF-KB) pathway. This review discusses the role of the TWEAK-Fn14 axis in several rheumatic diseases and the potential therapeutic benefits of modulation of the TWEAK-Fn14 pathway.