Growth factors and other paracrine signal molecules regulate communication between cells in all developing organs. During tooth morphogenesis, molecules in several conserved signal families mediate interactions both between and within the epithelial and mesenchymal tissue layers. The same molecules are used repeatedly during advancing development, and several growth factors are coexpressed in epithelial signaling centers. The enamel knots are signaling centers that regulate the patterning of teeth and are associated with foldings of the epithelial sheet. Different signaling pathways form networks and are integrated at many levels. Many targets of the growth factors have been identified, and mutations in several genes within the signaling networks cause defective tooth formation in both humans and mice.