Muscle remodeling is an important physiological process that promotes adaptive changes in cytoarchitecture and protein composition after exercise, aging, or disease conditions. Numerous transcription factors have been reported to regulate skeletal muscle homeostasis. NF-κB is a major pleiotropic transcription factor modulating immune, inflammatory, cell survival, and proliferating responses; however, its role in muscle development, physiology, and disease has just started to be elucidated. The current review article aims to summarize the literature on the role of NF-κB signaling in skeletal muscle pathophysiology, investigated over the last years using in vitro and more recently in vivo systems. Understanding the exact role of NF-κB in muscle cells will allow better therapeutic manipulations in the setting of human muscle diseases.