Recent advances in molecular and developmental genetics have provided tools for understanding evolutionary changes in the nature of the epithelial–mesenchymal interactions regulating the patterned outgrowth of the tooth primordia. Tissue recombination experiments in mice have identified the oral epithelium as providing the instructive information for the initiation of tooth development. Teeth were lost in birds for more than 80 million years ago, but despite their disappearance, a number of gene products and the requisite tissue interactions needed for tooth formation are found in the avian oral region. It is believed that the avian ectomesenchyme has lost the odontogenic capacity, whilst the oral epithelium retains the molecular signaling required to induce odontogenesis. In order to investigate the odontogenic capacity of the neural crest-derived mesenchyme and its potential activation of the avian oral epithelium, we have realized mouse neural tube transplantations to chick embryos to replace the neural crest cells of chick with those of mouse. Teeth are formed in the mouse/chick chimeras, indicating that timing is critical for the acquisition of the odontogenic potential by the epithelium and, furthermore, suggesting that odontogenesis is initially directed by species-specific mesenchymal signals interplaying with common epithelial signals. J. Exp. Zool. (Mol. Dev. Evol.) 306B, 2006. © 2006 Wiley-Liss, Inc.