Growing evidence suggests that the tumor necrosis factor superfamily (TNFSF) member TWEAK and its cognate receptor Fn14 play an important role in both physiological and pathological tissue remodeling. Herein, we review the various lines of experimental evidence that support the involvement of this ligand/receptor pair in triggering a wide range of cellular responses crucial to tissue remodeling, including angiogenic, proliferative, and inflammatory responses, and discuss the molecular mechanisms by which TWEAK/Fn14-induced tissue responses can lead to desired vs. undesired consequences in a context-dependent manner. We explore the key features of TWEAK-induced end-organ pathologies in various autoimmune disorders and the potential therapeutic benefits of TWEAK inhibition therein. We submit the viewpoint that TWEAK/Fn14-mediated pathogenic tissue remodeling represents an important, universal mechanism leading to various end-organ pathologies associated with autoimmune and inflammatory disorders. The highly specific and localized nature of its pathogenic contribution, therefore, makes the TWEAK/Fn14 pathway a unique and promising therapeutic target.