Hyperparathyroidism is a common disorder characterized by excessive secretion of parathyroid hormone (PTH) and resultant hypercalcemia. Primary hyperparathyroidism typically occurs in the setting of hypercellular growth of one or more parathyroid glands, associated with dysregulation of PTH release. Rarely, ectopic secretion of PTH by a nonparathyroid tumor has been described. Primary hyperparathyroidism may occur in the context of the inherited familial syndromes multiple endocrine neoplasia types 1, 2, and 4 (MEN 1, 2, and 4); the hereditary hyperparathyroidism–jaw tumor syndrome (HPT-JT); familial hypocalciuric hypercalcemia (FHH); and neonatal severe hyperparathyroidism (NSHPT), and, when it is the only recurrent clinical manifestation of disease within a family, familial isolated hyperparathyroidism (FIHPT). Most commonly, parathyroid neoplasia is sporadic and caused by a single benign adenoma. Insights into the molecular pathogenesis of both familial and sporadic primary hyperparathyroidism will be covered in this chapter.