The origin of active predation in vertebrates is associated with the rise of three major, uniquely derived developmental characteristics of the head: ( i ) migratory cranial neural crest cells (CNCCs) giving rise to most skeletal skull elements; ( ii ) expression of Dlx genes by CNCCs in the Hox -free first pharyngeal arch (PA1); and ( iii ) muscularization of PA1 derivatives. Here we show that these three innovations are tightly linked. Expression of Dlx genes by CNCCs is not only necessary for head skeletogenesis, but also for the determination, differentiation, and patterning of cephalic myogenic mesoderm leading to masticatory muscle formation. In particular, inactivation of Dlx5 and Dlx6 in the mouse results in loss of jaw muscles. As Dlx5/6 are not expressed by the myogenic mesoderm, our findings imply an instructive role for Dlx5/6 -positive CNCCs in muscle formation. The defect in muscularization does not result from the loss of mandibular identity observed in Dlx5/6 −/− mice because masticatory muscles are still present in EdnRA −/− mutants, which display a similar jaw transformation. The genesis of jaws and their muscularization should therefore be seen as an integrated Dlx -dependent developmental process at the origin of the vertebrate head. The role of Dlx genes in defining gnathostome jaw identity could, therefore, be secondary to a more primitive function in the genesis of the oral skeletomuscular system.