Uromodulin, also known as Tamm–Horsfall protein, is a kidney-specific glycoprotein produced by epithelial cells lining the thick ascending limb (TAL) and early distal convoluted tubule (DCT). It plays a multifaceted role in kidney physiology and disease, including modulating renal sodium handling through the regulation of tubular sodium transporters such as NKCC2 and NCC. Recent studies suggest a complex interaction between dietary sodium intake, uromodulin, and blood pressure. This review provides an updated overview of uromodulin's biology, focusing on its interaction with sodium-sensitive hypertension. Uromodulin has multiple forms, including intracellular, urinary, interstitial, and serum uromodulin, each with distinct functions. Intracellular uromodulin regulates protein trafficking and electrolyte handling, while urinary uromodulin forms polymers that maintain the water-impermeability of the TAL and protect against nephrolithiasis. Interstitial uromodulin acts as an immunoregulator, contributing to kidney injury and repair. Serum uromodulin is a biomarker of tubular integrity and mass, associated with renal and cardiovascular outcomes. Preclinical and genetic studies have linked uromodulin to sodium-sensitive hypertension, with specific UMOD variants increasing or decreasing the risk of hypertension. Clinical studies in healthy individuals and hypertensive patients suggest a potential link between uromodulin and sodium sensitivity, with uMOD levels acting as a prognostic marker and therapeutic target. However, methodological variations and inconsistent findings highlight the need for further research to define optimal measurement methods, consensus definitions, and the role of intracellular uromodulin.Uromodulin, also known as Tamm–Horsfall protein, is a kidney-specific glycoprotein produced by epithelial cells lining the thick ascending limb (TAL) and early distal convoluted tubule (DCT). It plays a multifaceted role in kidney physiology and disease, including modulating renal sodium handling through the regulation of tubular sodium transporters such as NKCC2 and NCC. Recent studies suggest a complex interaction between dietary sodium intake, uromodulin, and blood pressure. This review provides an updated overview of uromodulin's biology, focusing on its interaction with sodium-sensitive hypertension. Uromodulin has multiple forms, including intracellular, urinary, interstitial, and serum uromodulin, each with distinct functions. Intracellular uromodulin regulates protein trafficking and electrolyte handling, while urinary uromodulin forms polymers that maintain the water-impermeability of the TAL and protect against nephrolithiasis. Interstitial uromodulin acts as an immunoregulator, contributing to kidney injury and repair. Serum uromodulin is a biomarker of tubular integrity and mass, associated with renal and cardiovascular outcomes. Preclinical and genetic studies have linked uromodulin to sodium-sensitive hypertension, with specific UMOD variants increasing or decreasing the risk of hypertension. Clinical studies in healthy individuals and hypertensive patients suggest a potential link between uromodulin and sodium sensitivity, with uMOD levels acting as a prognostic marker and therapeutic target. However, methodological variations and inconsistent findings highlight the need for further research to define optimal measurement methods, consensus definitions, and the role of intracellular uromodulin.