Skeletal muscle development involves a multistep pathway in which mesodermal precursor cells are selected, in response to inductive cues, to form myoblasts that later withdraw from the cell cycle and differentiate. The transcriptional circuitry controlling muscle differentiation is intimately linked to the cell cycle machinery, such that muscle differentiation genes do not become transcribed until myoblasts have exited the cell cycle. Members of the MyoD and MEF2 families of transcription factors associate combinatorially to control myoblast specification, differentiation and proliferation. Recent studies have revealed multiple signaling systems that stimulate and inhibit myogenesis by altering MEF2 phosphorylation and its association with other transcriptional cofactors.