This review article discusses the role of STAT3 signaling in skeletal muscle regeneration and maintenance of muscle mass. STAT3 signaling plays a pivotal role in regulating the function of multiple cell types within the muscle tissue microenvironment. This includes muscle stem cells (MuSC), myofibers and macrophages. Indeed, we and others have recently shown that transient pharmacological inhibition of STAT3 promotes MuSC expansion and enhances tissue repair in vivo. STAT3 activation has also been directly linked to the loss of muscle mass in several chronic muscle wasting conditions. Muscle wasting is associated with several human diseases, thus there is a critical need to identify new potential targets for the development of efficient therapeutic approaches. STAT3 signaling is emerging as a critical regulator of skeletal muscle maintenance and regeneration, and as a nodal point of integration of extracellular cues emanating from the microenvironment. Overall, this could potentially lead to the development of more targeted and efficient therapeutic approaches.