Purpose of review Although uromodulin or Tamm-Horsfall protein was discovered over 60 years ago, its functional role in humans remains unclear. This review highlights new studies elucidating the clinical correlates of uromodulin, its association with kidney function decline, nephrolithiasis and urinary host defense. Recent findings Uromodulin is evolutionarily conserved and has multiple functional roles. In large population studies, higher levels of uromodulin are associated with higher estimated glomerular filtration rate (eGFR) and kidney size, possibly indicating greater kidney functional reserve. Greater uromodulin excretion is associated with markers of volume overload such as fractional excretion of uric acid, sodium and chloride, indicating a possible role in salt and water retention. Recent evidence also suggests that higher uromodulin levels are associated with lower risk of eGFR decline, death and possibly a lower risk of acute kidney injury. Higher levels of uromodulin are associated with lower risk of urinary tract infections in older adults. Serum uromodulin levels are positively associated with eGFR, although its functional role remains unclear. Summary Over the last decade, we have begun to understand the functional role of uromodulin in health and disease. Large prospective studies in generalizable populations are needed to confirm these preliminary results, evaluate the clinical utility of measuring uromodulin and examine whether levels of this biomarker can be altered for therapeutic benefit.