Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism due to pathogenic activating variants in the gene encoding the extracellular calcium-sensing receptor (CaSR). These variants increase the CaSR’s sensitivity to circulating calcium, leading to inadequate parathyroid hormone (PTH) secretion and decreased renal calcium and magnesium reabsorption. Affected individuals experience hypocalcemia, hypercalciuria, hypomagnesemia, and hyperphosphatemia. Clinical features are variable, ranging from asymptomatic to paresthesia and muscle cramps to laryngospasm and seizures. Standard-of-care (SoC) therapy with calcium and active Vitamin D may exacerbate the hypercalciuria, resulting in renal morbidity. Calcilytics, acting as negative allosteric modulators, decrease the sensitivity of CaSRs to extracellular calcium. In a small proof-of-principle study, the investigational IV calcilytic NPSP795 induced a dose-dependent increase in PTH secretion when administered briefly to 5 adults with ADH1. We subsequently conducted a Phase 2b open-label study of the oral investigational calcilytic encaleret, in which 13 adults with ADH1 discontinued SoC and underwent 1- or 2-week inpatient dose-finding and safety/tolerability periods followed by 24 weeks of outpatient dosing and a long-term extension (LTE). Encaleret increased mean intact PTH, albumin-corrected calcium, and blood magnesium, while decreasing blood phosphorus and renal calcium excretion; these effects continue to be seen after up to 5.5 years of continuous treatment. An ongoing Phase 3 multicenter international open-label randomized trial (CALIBRATE) comparing encaleret with SoC in 67 adults with ADH1 achieved its primary endpoint in October 2025, and a New Drug Application is currently under review. Encaleret has been well-tolerated with minimal treatment-related AEs, none of which have led to study withdrawal. Importantly, as this is a disorder affecting individuals from birth, a Phase 2/3 multicenter single-arm study in children (CALIBRATE-PEDS) is currently underway. These studies represent a paradigm shift in hypoparathyroidism treatment, using a molecularly targeted, precision medicine approach for the treatment of ADH1.