ABSTRACT The molecular events of odontogenic induction are beginning to be elucidated, but until now nothing was known about the molecular basis of the patterning of the dentition. A role for Dlx-1 and Dlx-2 genes in patterning of the dentition has been proposed with the genes envisaged as participating in an ‘odontogenic homeobox gene code’ by specifying molar development. This proposal was based on the restricted expression of the genes in molar ectomesenchyme derived from cranial neural crest cells prior to tooth initiation. Mice with targeted null mutations of both Dlx-1 and Dlx-2 homeobox genes do not develop maxillary molar teeth but incisors and mandibular molars are normal. We have carried out heterologous recombinations between mutant and wild-type maxillary epithelium and mesenchyme and show that the ectomesenchyme underlying the maxillary molar epithelium has lost its odontogenic potential. Using molecular markers of branchial arch neural crest (Barxl) and commitment to chondrogenic differentiation (Sox9), we show that this population alters its fate from odontogenic to become chondrogenic. These results provide evidence that a subpopulation of cranial neural crest is specified as odontogenic by Dlx-1 and Dlx-2 genes. Loss of function of these genes results in reprogramming of this population of ectomesenchyme cells into chondrocytes. This is the first indication that the development of different shaped teeth at different positions in the jaws is determined by independent genetic pathways.