Skeletal muscle formation and growth require the fusion of myoblasts to form multinucleated myofibers or myotubes, but few molecules are known to regulate myoblast fusion in mammals. The transcription factor NFATc2 controls myoblast fusion at a specific stage of myogenesis after the initial formation of a myotube and is necessary for further cell growth. By examining genes regulated by NFATc2 in muscle, this study identifies the cytokine IL-4 as a molecular signal that controls myoblast fusion with myotubes. Muscle cells lacking IL-4 or the IL-4alpha receptor subunit form normally but are reduced in size and myonuclear number. IL-4 is expressed by a subset of muscle cells in fusing muscle cultures and requires the IL-4alpha receptor subunit on myoblasts to promote fusion and growth. These data demonstrate that following myotube formation, myotubes recruit myoblast fusion by secretion of IL-4, leading to muscle growth.