During palatal fusion, the midline epithelial seam between the palatal shelves degrades to achieve mesenchymal confluence. Morphological and molecular evidence support the theory that the epithelial-mesenchymal transition is one mechanism that regulates palatal fusion. It appears that transforming growth factor (TGF)-beta signaling plays a role in palatal EMT. TGFbeta3 is the main inducer in palatal fusion and activates both Smad-dependent and -independent signaling pathways, including the key EMT transcription factors, Lef1, Twist, and Snail1, in the MEE prior to the palatal EMT program. The roles and interactions among these transcription factors will be discussed.