Uromodulin is produced in the thick ascending limb, but little is known about regulation of its excretion in urine. Using mouse and cellular models, we demonstrate that excretion of uromodulin by thick ascending limb cells is increased or decreased upon inactivation or activation of the calcium-sensing receptor (CaSR), respectively. These effects reflect changes in uromodulin trafficking and likely involve alterations in intracellular cyclic adenosine monophosphate (cAMP) levels. Administration of the CaSR agonist cinacalcet led to a rapid reduction of urinary uromodulin excretion in healthy subjects. Modulation of uromodulin excretion by the CaSR may be clinically relevant considering the increasing use of CaSR modulators.