Acellular cementum (AC) is critical for dental attachment and periodontal function. This chapter emphasizes how insights into cementum's nature have increased through human disease and experimental animal models. X-linked hypophosphatemia (XLH) is the most common form of hereditary rickets, in which low circulating phosphate and altered vitamin D metabolism are associated with skeletal and dental mineralization defects. AC thickness is reduced in XLH, and periodontal function may be affected. Inorganic pyrophosphate is a circulating inhibitor of mineralization. The inherited disorder, hypophosphatasia (HPP), is characterized by increased pyrophosphate levels, leading to skeletal and dental hypomineralization. AC is mainly affected by HPP, and premature loss of deciduous and permanent teeth is a common result. Conversely, a decrease in pyrophosphate results in increased cementum thickness. Extracellular matrix proteins also regulate cementum formation. Bone sialoprotein (BSP) is a component of cementum. Deletion of BSP in genetically edited mice results in reduced or absent AC, leading to periodontal destruction.