In “Genetic Disorders of Calcium, Phosphorus, and Bone Homeostasis” the mechanisms that regulate calcium and phosphorus metabolism and bone formation, resorption, strength, and resilience are discussed. The physiologic function and roles of vitamin D metabolites, parathyroid hormone, calcitonin, and other factors (e.g., phosphatonins, receptor activator of nuclear factor kappa B ligand, osteoprotegerin, et cetera) are presented. The functional effects of osteoblasts, osteocytes, and osteoclasts upon bone matrix and hydroxyapatite and their roles in bone development and maintenance of bone strength are described. The roles of alkaline phosphatase, collagen, non-collagenous proteins (e.g., osteocalcin, osteonectin, small integrin-binding ligand, N-linked glycoproteins such as matrix extracellular glycoprotein and dentin matrix protein that bind avidly to hydroxyapatite, the calcium phosphate crystal) in the maintenance of bone integrity and strength are examined. Genetic disorders resulting in hypocalcemia, hypercalcemia, or abnormalities of bone mineralization are then described. Variants of genes that regulate development of the parathyroid glands, synthesis or biologic effectiveness of parathyroid hormone, metabolism of vitamin D, and the calcium sensing receptor may result in hypocalcemia. Mutations in AIRE (Autoimmune regulator) lead to autosomal dominant hypoparathyoidism through dysregulation of the immune system resulting in autoimmune destruction of the parathyroid glands. Among other causes, deleterious variations in genes that regulate the expression of the calcium sensing receptor, differentiation of the parathyroid glands, production of the seven transmembrane, G-protein associated parathyroid hormone receptor, metabolism of vitamin D and continuous gene deletions (e.g., Williams-Beuren syndrome, chromosome 7q11.23) may result in hypercalcemia. Mutations in genes that regulate collagen synthesis and removal, intestinal and renal calcium, phosphorus, and hydrogen transport, and skeletal hydroxyapatite deposition and resorption may result in decreased or excessive bone mineralization – both often manifested clinically by increased bone fragility.