Endothelin-A (ET_A) is a G-protein-coupled receptor expressed in the neural crest-derived mesenchyme of the pharyngeal arches during craniofacial development. Targeted deletion of the ET_A receptor or its ligand endothelin-1 (ET-1) causes cleft palate and hypoplasia of the mandible, otic cup, and tympanic ring. Previously we showed that Gα_q/Gα₁₁-null mice die around E11.0, whereas Gα_q^(−/−)Gα₁₁^(+/−) mice survive to birth with hypomorphic phenotypes similar to, but less severe than, ET_A or ET-1-null mice. To determine whether ET-1 signaling is transduced by Gα_q/Gα₁₁ proteins, we examined the expression patterns of several ET-1 dependent and independent transcription factors in Gα_q/Gα₁₁-deficient embryos. Expression of genes encoding the ET-1-dependent transcription factors Dlx3, Dlx6, dHAND, and eHAND was specifically downregulated in the pharyngeal arches of Gα_q/Gα₁₁-deficient mice. In contrast, pharyngeal arch expression of the homeobox gene Msx1, which is not regulated by ET-1 signaling, was maintained in these embryos. We conclude that the Gα_q and Gα₁₁ proteins serve as the intracellular mediators of ET-1 signaling in the pharyngeal arch mesenchyme.