This review highlights a number of advances towards understanding the sequential developmental cascade of events beginning in the oral ectodermally-derived odontogenic placode and culminating in the formation of the mineralized enamel extracellular matrix. Recent discoveries of growth factors, growth factor receptors and transcription factors associated with instructive epithelial-mesenchymal interactions and subsequent controls for ameloblast cell differentiation are reviewed. The relationship between ameloblast cytology, terminal differentiation and biochemical phenotype are discussed. The tissue-specific gene products characteristic of the ameloblast phenotype as well as their possible functions in formation of the enamel matrix are analyzed as well as the role of maturation-stage ameloblast cells in controlling enamel biomineralization. Finally, pathological conditions in which alterations in the ameloblast or specific gene products result in an abnormal enamel phenotype are reviewed. Clearly, the scientific progress achieved in the last few years concerning the molecular determinants involved in tooth development has been remarkable. However, there remains considerable lack of knowledge regarding the precise mechanisms that control ameloblast differentiation and enamel biomineralization. Anticipated progress continues to require increased international cooperation and collaborations as well as increased utilization of structural biology investigations of enamel extracellular matrix proteins.