TWEAK is a multifunctional cytokine that controls many cellular activities including proliferation, migration, differentiation, apoptosis, angiogenesis and inflammation. TWEAK acts by binding to Fn14, a highly inducible cell-surface receptor that is linked to several intracellular signalling pathways, including the nuclear factor-κB (NF-κB) pathway. The TWEAK–Fn14 axis normally regulates various physiological processes, in particular it seems to play an important, beneficial role in tissue repair following acute injury. Furthermore, recent studies have indicated that TWEAK–Fn14 axis signalling may contribute to cancer, chronic autoimmune diseases and acute ischaemic stroke. This Review provides an overview of TWEAK–Fn14 axis biology and summarizes the available data supporting the proposal that both TWEAK and Fn14 should be considered as potential targets for the development of novel therapeutics.