Canonical Wnt/β-catenin signaling regulates the activation of the myogenic determination gene Myf5 at the onset of myogenesis, but the underlying molecular mechanism is unknown. Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz)receptors (Fz1 and/or Fz6), through the canonical β-catenin pathway, in the epaxial domain of newly formed somites. We show that Myf5activation is dramatically reduced by blocking the Wnt/β-catenin pathway in somite progenitor cells, whereas expression of activated β-catenin is sufficient to activate Myf5 in somites but not in the presomitic mesoderm. In addition, we identified Tcf/Lef sequences immediately 5′ to the Myf5 early epaxial enhancer. These sites determine the correct spatiotemporal expression of Myf5 in the epaxial domain of the somite, mediating the synergistic action of the Wnt/β-catenin and the Shh/Gli pathways. Taken together, these results demonstrate that Myf5is a direct target of Wnt/β-catenin, and that its full activation requires a cooperative interaction between the canonical Wnt and the Shh/Gli pathways in muscle progenitor cells.