In mice, the homeoproteins Six4 and Six1 are co-expressed during myogenesis in the myotome, limb bud mesenchyme and other muscle precursors. However,although Six1-null mouse embryos show some mild muscle defects,muscle development is normal in Six4-null mice. On p. 2235, Grifone and co-workers report that the muscle defect seen in Six1-null mice is amplified in Six1 Six4 double knockout mice. These mice have no limb muscles because Pax3 is downregulated in a ventral region of the somites that gives rise to the progenitors of the hypaxial muscle, from which limb muscles form. Consequently, the muscle precursors fail to migrate properly, lose their myogenic identity and apoptose. The researchers also detail how the absence of Six1 and Six4 affects myogenic regulatory factors throughout the developing musculature and conclude that the overlapping functions of Six1 and Six4 play several different roles during skeletal myogenesis.