Pyrophosphate (PP_i) serves as a potent and physiologically important regulator of mineralization, with systemic and local concentrations determined by several key regulators, including:​ tissue-nonspecific alkaline phosphatase (ALPL gene;​ TNAP protein), the progressive ankylosis protein (ANKH;​ ANK), and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1;​ ENPP1). Results to date have indicated important roles for PP_i in cementum formation, and we addressed several gaps in knowledge by employing genetically edited mouse models where PP_i metabolism was disrupted and pharmacologically modulating PP_i in a PP_i-deficient mouse model. We demonstrate that acellular cementum growth is inversely proportional to PP_i levels, with reduced cementum in Alpl KO (increased PP_i levels) mice and excess cementum in Ank KO mice (decreased PP_i levels). Moreover, simultaneous ablation of Alpl and Ank results in reestablishment of functional cementum in dKO mice. Additional reduction of PP_i by dual deletion of Ank and Enpp1 does not further increase cementogenesis, and PDL space is maintained in part through bone modeling/remodeling by osteoclasts. Our results provide insights into cementum formation and expand our knowledge of how PP_i regulates cementum. We also demonstrate for the first time that pharmacologic manipulation of PP_i through an ENPP1-Fc fusion protein can regulate cementum growth, supporting therapeutic interventions targeting PP_i metabolism.