IKKβ/NF-κB activation causes severe muscle wasting in mice. Activation of NF-κB through muscle-specific transgenic expression of activated IKKβ (MIKK) leads to profound muscle wasting resembling clinical cachexia. In contrast, no overt phenotype is observed upon muscle-specific inhibition of NF-κB through expression of IκBα superrepressor (MISR). Muscle loss is due to accelerated protein breakdown via ubiquitin-dependent proteolysis. Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, is increased in MIKK mice. Pharmacological or genetic inhibition of the IKKβ/NF-κB/MuRF1 pathway reverses muscle atrophy. Denervation- and tumor-induced muscle loss are substantially reduced and survival rates improved by NF-κB inhibition in MISR mice, consistent with a critical role for NF-κB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy. Muscle wasting is a major feature of cachexia associated with various pathologies. NF-κB in muscle is activated by disuse or sepsis and may play a role in the pathogenesis of these conditions. In vitro blockade inhibits protein loss in C2C12 myotubes. NF-κB activation in MIKK mice leads to increased NF-κB activity, matching that seen in a model of muscle atrophy. MIKK mice exhibit profound muscle wasting, while MISR mice lack an overt phenotype. MIKK mice have reduced muscle mass due to decreased skeletal muscle mass. Muscle fibers in MIKK mice are smaller than in wild-type mice, with no evidence of central nuclei, inflammatory infiltrates, or fibrosis. Cross-sectional areas of muscle fibers in MIKK mice decrease with age. Inhibition of NF-κB in MIKK mice reverses the phenotype. High-dose salicylates inhibit IKKβ and NF-κB, reversing the MIKK phenotype. MIKK mice show increased protein catabolism, with elevated amino acid and metabolite concentrations in urine. Protein breakdown and synthesis assays show increased catabolism in MIKK mice. The proteasome inhibitor MG-132 reduces protein breakdown in MIKK mice, suggesting ubiquitin-proteasome pathways mediate muscle degradation. NF-κB activates proteolysis but not cytokine signaling in muscle. MuRF1 expression is increased in MIKK mice and reduced in MISR mice. MuRF1 is an NF-κB target, and its deletion reduces muscle wasting. NF-κB inhibition protects against denervation and cancer cachexia-induced muscle atrophy. NF-κB activation in skeletal muscle causes muscle atrophy, while inhibition prevents it. NF-κB inhibition in MISR mice reduces muscle loss and improves survival. NF-κB activation in MIKK mice leads to increased MuRF1 expression,IKKβ/NF-κB activation causes severe muscle wasting in mice. Activation of NF-κB through muscle-specific transgenic expression of activated IKKβ (MIKK) leads to profound muscle wasting resembling clinical cachexia. In contrast, no overt phenotype is observed upon muscle-specific inhibition of NF-κB through expression of IκBα superrepressor (MISR). Muscle loss is due to accelerated protein breakdown via ubiquitin-dependent proteolysis. Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, is increased in MIKK mice. Pharmacological or genetic inhibition of the IKKβ/NF-κB/MuRF1 pathway reverses muscle atrophy. Denervation- and tumor-induced muscle loss are substantially reduced and survival rates improved by NF-κB inhibition in MISR mice, consistent with a critical role for NF-κB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy. Muscle wasting is a major feature of cachexia associated with various pathologies. NF-κB in muscle is activated by disuse or sepsis and may play a role in the pathogenesis of these conditions. In vitro blockade inhibits protein loss in C2C12 myotubes. NF-κB activation in MIKK mice leads to increased NF-κB activity, matching that seen in a model of muscle atrophy. MIKK mice exhibit profound muscle wasting, while MISR mice lack an overt phenotype. MIKK mice have reduced muscle mass due to decreased skeletal muscle mass. Muscle fibers in MIKK mice are smaller than in wild-type mice, with no evidence of central nuclei, inflammatory infiltrates, or fibrosis. Cross-sectional areas of muscle fibers in MIKK mice decrease with age. Inhibition of NF-κB in MIKK mice reverses the phenotype. High-dose salicylates inhibit IKKβ and NF-κB, reversing the MIKK phenotype. MIKK mice show increased protein catabolism, with elevated amino acid and metabolite concentrations in urine. Protein breakdown and synthesis assays show increased catabolism in MIKK mice. The proteasome inhibitor MG-132 reduces protein breakdown in MIKK mice, suggesting ubiquitin-proteasome pathways mediate muscle degradation. NF-κB activates proteolysis but not cytokine signaling in muscle. MuRF1 expression is increased in MIKK mice and reduced in MISR mice. MuRF1 is an NF-κB target, and its deletion reduces muscle wasting. NF-κB inhibition protects against denervation and cancer cachexia-induced muscle atrophy. NF-κB activation in skeletal muscle causes muscle atrophy, while inhibition prevents it. NF-κB inhibition in MISR mice reduces muscle loss and improves survival. NF-κB activation in MIKK mice leads to increased MuRF1 expression,