MEF2 transcription factors are well-established regulators of muscle development. We have discovered an unanticipated role for MEF2C in the neural crest, where tissue-specific inactivation results in neonatal lethality due to severe craniofacial defects. We show that MEF2C is required for expression of the Dlx5, Dlx6, and Hand2 transcription factor genes in the branchial arches, and we identify a branchial arch-specific enhancer in the Dlx5/6 locus, which is activated synergistically by MEF2C and Dlx5, demonstrating that these factors interact to induce transcription. Mef2c and Dlx5/6 also interact genetically. Mice heterozygous for either Dlx5/6 or Mef2c are normal at birth and survive to weaning. By contrast, heterozygosity for both Mef2c and Dlx5/6 results in defective palate development and neonatal lethality. Taken together, the studies presented here define a feed-forward transcriptional circuit between the MADS-box transcription factor MEF2C and the homeodomain transcription factors Dlx5 and Dlx6 in craniofacial development.