Extracellular calcium ion concentration is tightly regulated through the actions of parathyroid hormone (PTH) on kidney and bone. The intact peptide is secreted by the parathyorid glands at a rate that is inversely related to the prevailing extracellular calcium ion concentration [1]. Hypercalcaemic or hypocalcaemic disorders can be classified according to whether they arise from an excess or deficiency of PTH, a defect in the PTH-receptor (ie the PTH/PTHrP receptor), or an insensitivity to PTH caused by defects down-stream of the PTH/PTHrP receptor (Table 1). Recent advances in understanding the biological importance of key proteins involved in the regulation of PTH secretion and the responsiveness to PTH in target tissues has led to the identification of molecular defects in a variety of disorders, and thus have enabled the characterization of some of the mechanisms involved in the regulation of parathyroid gland development, parathyroid cell proliferation, PTH secretion, and PTH-mediated actions in target tissues [1, 2]. Thus, contrasting mutations in the calcium-sensing receptor gene have been reported in patients with familial benign (hypocalciuric) hypercalcaemia (FBH or FHH), or neonatal severe hyperparathyrodism and autosomal dominant hypocalcaemia. Furthermore, the roles of the oncogene PRAD1, which encodes a novel cyclin, and of the multiple endocrine neoplasia type 1 (MEN1) gene in the pathogenesis of some parathyroid tumours have been revealed (Fig. 1). In addition, mutations in the PTH gene and the mitochondrial genome have been demonstrated to be associated with some forms of hypoparathyroidism, mutations in the PTH/PTHrP receptor gene have been identified in patients with two rare genetic disorders, Jansen’s and Blomstrand’s chondrodysplasia, and mutations that regulate expression or function α chain of the stimulatory G protein (Gsα) have been found in individuals with McCune-Albright-syndrome, pseudohypoparathyroidism type Ia, pseudo-pseudohypoparathyroidism and pseudohypoparathyroidism type Ib. Furthermore, candidate genes have been identified for the DiGeorge syndrome and the chromosomal locations for the susceptibility genes that are responsible for the less frequent variants of FBH and Williams syndrome have been established [1]. Molecular genetic studies thus have provided unique opportunities to elucidate the pathogenesis of parathyroid disorders and these will be reviewed in this chapter.