Dentin sialoprotein (DSP) and dentin phosphoprotein (DPP) play distinct roles during dentinogenesis. Both dentin extracellular matrix proteins are cleaved products of dentin sialophosphoprotein (DSPP), an important odontoblastic differentiation marker. Mutations of the DSPP gene in human and mouse cause mineralization defects in teeth. During odontogenesis, DSPP is predominantly expressed in developing teeth whereas its expression is much lower in other tissues. Therefore, DSPP serves as a unique model to study the mechanisms of spatial-temporal and tissue-specific gene regulation associated with dentinogenesis. Both in vitro and in vivo promoter analysis studies have shown that DSPP transcription is controlled by a series of growth factors and transcriptional factors as well as local factors. Some factors up-regulate DSPP expression whereas others down-regulate its transcription. Spatialtemporal DSPP expression at different stages of tooth developmental is mediated by a complex network of growth factors and transcription factors. Beyond the role of biomineralization, recent studies have demonstrated that both DSP and DPP may function as intracellular transductors. DPP is able to induce tooth- and bone-related gene expressions via the MAPK and Smad signaling pathways while DSP binds to cell membrane proteins, resulting in activation of intracellular protein kinases. This data may provide novel insights into the roles of DSP and DPP in cell proliferation and differentiation besides biomineralization.