Odontogenesis is a complex process in which the interplay of signaling cascades of the epithelium and mesenchyme is critical. Evidence for the involvement of Runx2--a well-known osteogenic master transcription factor--in odontogenesis, has been accumulating. Haploinsufficiency of Runx2 in humans results in cleido-cranial dysplasia (CCD), characterized by supernumerary teeth; in Runx2-/- mice, molar odontogenesis does not proceed beyond the late bud stage. In this article, we discuss the role of Runx2 in tooth development, specifically in the signaling interplay of the epithelium and mesenchyme during the transition from bud stage to cap stage. Runx2 is an important molecule of the dental mesenchyme; its expression is induced by epithelial fibroblast growth factor (FGF), and it is involved in regulating the induction of mesenchymal signaling back to the dental epithelium for epithelial morphogenesis. In addition, we discuss the role of the two major isoforms of Runx2, and other Runx family genes, in odontogenic processes.