Uromodulin, also known as Tamm-Horsfall protein, is a glycoprotein expressed exclusively by renal tubular cells lining the thick ascending limb of the loop of Henle. Although the physiologic functions of this protein remain elusive, significant progress has been made during the last decade that highlights the importance of uromodulin in the pathophysiology of various diseases, such as medullary cystic kidney disease, urinary tract infections, and nephrolithiasis. Meanwhile, there is renewed interest in the role of uromodulin in kidney injury, both acute and chronic. In this article, we review the existing evidence that supports a role for uromodulin in acute kidney injury, chronic kidney disease, and renal inflammation. Contrary to the conventional view of uromodulin as an instigator in kidney injury, new data from uromodulin knockout mice show a protective role for this protein in acute kidney injury, possibly through downregulating interstitial inflammation. In chronic kidney disease, uromodulin excretion, when adjusted for kidney function, is increased; the significance of this is unclear. Although it has been suggested that uromodulin exacerbates progressive kidney injury, we propose that the elevation in uromodulin secretion is instead reactive to injury and reflects an increase of uromodulin in the renal parenchyma, where it slows the injury process.