For several decades, the transcription factor MEF2 (myocyte enhancer factor-2) has been known as a master regulator of myogenesis that orchestrates the first step in muscle formation: the differentiation of myoblasts into myocytes. Because of its importance during myoblast differentiation, the potential roles of MEF2 during later steps of myogenesis, in particular myocyte fusion, could not be properly investigated. Our recent findings filled that gap as we recently unravelled a key role of MEF2 in myocyte fusion both in vitro and in vivo. Mechanistically, we identified the PP2A-Bδ phosphatase as a key enzyme regulating MEF2 activity specifically during fusion, but not differentiation. We showed that by controlling phosphorylation of HDAC4, a known repressor of MEF2, PP2A-Bδ regulates the transcription of a subset of MEF2-dependent genes involved solely in myocyte fusion. Our observations demonstrate that, in contrast to the historical paradigm, MEF2 controls both early (i.e., the myoblast differentiation) and late (i.e., the myocyte fusion) steps of myogenesis with PP2A-Bδ allowing discrimination between both functions. Because PP2A holoenzymes exhibit high substrate specificity, our findings point towards novel therapeutic options for various myopathies characterized by defects in normal fusion, such as muscular dystrophies.