Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor (TNF) superfamily of structurally related cytokines. Full-length, membrane-anchored TWEAK can be found on the surface of many cell types and a smaller, biologically active form, generated via proteolytic processing, has also been detected in the extracellular milieu. TWEAK acts via binding to a recently identified TNF receptor superfamily member named fibroblast growth factor-inducible 14 (Fn14). It has been demonstrated that TWEAK binding to the Fn14 receptor, or constitutive Fn14 overexpression, activates the nuclear factor-kappaB signaling pathway, which is known to play an important role in immune and inflammatory processes, oncogenesis, and cancer therapy resistance. In this article, we review recent studies indicating that TWEAK and Fn14 may be potential regulators of human tumorigenesis.