Enamel, a highly mineralized tissue, possesses a unique formation process unparalleled among all mineralized tissues, serving as the primary protective layer for dental structures. Its pertinence to oral health is underscored by the effects of mineralization defects, evident in conditions like amelogenesis imperfecta and fluorosis. Central to the enamel formation process are amelogenin proteins, which not only guide the formation of initial hydroxyapatite (HAP) crystals but also undergo hydrolysis from the secretory to maturation stages. This hydrolysis, along with the subsequent matrix removal, is modulated by matrix pH cycling, with disruptions in this cycling invariably resulting in hypomineralized enamel. The intricate interrelationships between amelogenin hydrolysis, ameloblast modulation, and matrix pH cycling, however, remain ambiguous. Our forthcoming research endeavors to elucidate these nuances, targeting 1) the implications of amelogenin hydrolysis on maturation stage ameloblast (MAB) cell functionality; 2) the determinative roles of extracellular calcium and pH in MAB ameloblast morphogenesis; and 3) the directive influence of matrix pH on amelogenin structure and its subsequent removal in the mineralizing matrix.