Odontoblast terminal differentiation occurs according to a tooth-specific pattern and implies both temporo-spatially regulated epigenetic signaling and the expression of specific competence. Differentiation of odontoblasts (withdrawal from the cell cycle, cytological polarization, and secretion of predentin/dentin) is controlled by the inner dental epithelium, and the basement membrane (BM) plays a major role both as a substrate and as a reservoir of paracrine molecules. Cytological differentiation implies changes in the organization of the cytoskeleton and is controlled by cytoskeleton-plasma membrane-extracellular matrix interactions. Fibronectin is re-distributed during odontoblast polarization and interacts with cell-surface molecules. A nonintegrin 165-kDa fibronectin-binding protein, transiently expressed by odontoblasts, is involved in microfilament reorganization. Growth factors (TGFβ1,2,3/BMP2,4, and 6), expressed in tooth germs, signal differentiation. Systemically derived molecules (IGF1) may also intervene. IGF1 stimulates cytological but not functional differentiation of odontoblasts: The two events can thus be separated. Immobilized TGFβ1 (combined with heparin) induced odontoblast differentiation. Only immobilized TGFβ1 and 3 or a combination of FGF1 and TGFβ1 stimulated the differentiation of functional odontoblasts over extended areas and allowed for maintenance of gradients of differentiation. Presentation of active molecules in vitro appeared to be of major importance; the BM should fulfill this role in vivo by immobilizing and spatially presenting TGF(3s. Attempts are being made to investigate the mechanisms which spatially control the initiation of odontoblast differentiation and those which regulate its propagation. Analysis of molar development suggested that odontoblast differentiation and crown morphogenesis are interdependent, although the possibility of co-regulation requires further investigation.