ABSTRACT In all vertebrates, the secondary palate arises as bilateral outgrowths from the maxillary processes. In birds and most reptiles, these palatal shelves grow initially horizontally, but do not fuse with each other resulting in physiological cleft palate. In crocodilians, shelf fusion occurs resulting in an intact secondary palate. Mammalian palatal shelves initially grow vertically down the side of the tongue, but elevate at a precise time to a horizontal position above the dorsum of the tongue and fuse with each other to form an intact palate. Palatal shelf-elevation is the result of an intrinsic shelf elevating force, chiefly generated by the progressive accumulation and hydration of hyaluronic acid. In all vertebrates the nasal epithelium differentiates into pseudostratified ciliated columnar cells and the oral epithelia differentiates into stratified squamous cells, but the medial edge epithelial (MEE) phenotype differs in different groups. In mammals, the MEE of opposing shelves adhere to each other to form an epithelial seam which then disrupts by cell death and cell migration into the mesenchyme accompanied by an epitheliomesenchymal transformation. In birds, the MEE keratinize resulting in cleft palate whereas, in alligators, the MEE migrate onto the nasal aspect of the palate. In all vertebrates, this regional, temporal and species-specific epithelial differentiation is specified by the underlying mesen-chyme. Signalling of this interaction is complex but involves both extracellular matrix and soluble factors e.g. minor collagen types, tenascin, EGF, TGFα, TGFβ, PDGF, FGF. These soluble growth factors have a biphasic effect: directly on the epithelia and on the mesenchyme where they stimulate or inhibit cell division and synthesis of specific extracellular matrix molecules. The extracellular matrix molecules (and bound growth factors) synthesized by the mesenchymal cells may then directly affect the epithelium. These signals cause differential gene expression via second messenger systems e.g. cAMP, cGMP, Ca2+, pH, pl etc. Molecular markers for nasal, medial and oral epithelial cell differentiation include the types of cytokeratin intermediate filaments and specific cell surface molecules recognized by monoclonal antibodies: the genes for such molecules are probably expressed in response to mesenchymal signals. Using such an approach, it is possible to go from a morphological description of palate development to a cellular analysis of the mechanisms involved and then to identification of candidate genes that may be important for screening and diagnosis of cleft palate.