Chronic disease states are associated with elevated levels of inflammatory cytokines that have been demonstrated to lead to severe muscle wasting. A mechanistic understanding of muscle wasting is hampered by limited in vivo cytokine models which can be applied to emerging mouse mutants as they are generated. We developed a simple and novel approach to induce adult mouse skeletal muscle wasting based on direct gene transfer of an expression vector encoding the secreted form of the murine tumor necrosis factor-α (mTNFα). This procedure results in the production of elevated levels of circulating mTNFα followed by body weight loss, upregulation of Atrogin1, and muscle atrophy, including muscles distant from the site of gene transfer. We also found that mTNFα gene transfer resulted in a significant inhibition of regeneration following muscle injury. We conclude that in addition to being a potent inducer of cachexia, TNFα is a potent inhibitor of myogenesis in vivo. genesis 43:120–128, 2005. © 2005 Wiley-Liss, Inc.