Skeletal muscle is one of the largest functional tissues in the human body; it is highly plastic and responds dramatically to anabolic and catabolic stimuli, including weight training and malnutrition, respectively. Excessive loss of muscle mass, or atrophy, is a common symptom of many disease states with severe impacts on prognosis and quality of life. TNF-like weak inducer of apoptosis (TWEAK) and its cognate receptor, fibroblast growth factor-inducible 14 (Fn14) are an emerging cytokine signaling pathway in the pathogenesis of muscle atrophy. Upregulation of TWEAK and Fn14 has been described in a number of atrophic and injured muscle states; however, it remains unclear whether they are contributing to the degenerative or regenerative aspect of muscle insults. The current review focuses on the expression and apparent downstream outcomes of both TWEAK and Fn14 in a range of catabolic and anabolic muscle models. Apparent changes in the signaling outcomes of TWEAK-Fn14 activation dependent on the relative expression of both the ligand and the receptor are discussed as a potential source of divergent TWEAK-Fn14 downstream effects. This review proposes both a physiological and pathological model of TWEAK-Fn14 signaling. Further research is needed on the switch between these states to develop therapeutic interventions for this pathway.