Skeletal muscle and the immune system are intimately related: this close connection facilitates muscle’s ability to respond to environmental stresses rapidly. Immune cells and inflammatory cytokines are important in the promotion of muscle protein turnover, both in response to direct muscle injury and to enable amino acid delivery to other tissues. In aging, there is evidence of increased inflammatory signaling systemically, and of disordered cytokine responses to injury. In chronic inflammatory diseases and animal models of muscle wasting, however, cytokine blockade has not consistently reversed muscle wasting. Recent evidence suggests that key skeletal muscle atrophy and differentiation pathways are downstream of the NFkB/IL-1/TNF inflammatory cascade, and act via the activin receptor to inhibit myotube differentiation and the regenerative response to injury. Taken together, these data suggest that direct cytokine inhibition may not be sufficient to repair muscle atrophy or sarcopenia, and that additional anti-catabolic or anabolic treatments will be needed.