Tamm-Horsfall protein (THP) is exclusively produced by renal tubular cells of the distal loop of Henle and is the most abundant urinary protein in mammals. The physiological function of THP has remained elusive for over half a century; however, new lines of research position it as a central antimicrobial molecule combating urinary tract infection (UTI). Furthermore, the genetic basis of familial juvenile hyperuricemic nephropathy (FJHN), glomerulocystic kidney disease (GCKD) and autosomal dominant medullary cystic kidney disease 2 (MCKD2) has been recently attributed to mutations within the THP gene. In these clinical conditions misfolded THP accumulates in the tubular cells, ultimately leading to overt renal insufficiency. UTI is the most common nonepidemic bacterial infection in humans, where both innate and adaptive components of the immune system as well as the bladder epithelium are involved in its prevention and clearance. Since the urogenital tract is devoid of typical physical barriers such as mucus or a ciliated epithelium, soluble mediators with potent anti-bacterial capabilities might exist. Recently, genetic ablation of the THP gene was shown to lead to severe infection and lethal pyelonephritis in experimental models of UTI. In addition, mounting evidence indicates that, beyond simply a direct antimicrobial activity, THP is a potent immunoregulatory molecule that induces specific THP-directed cell-mediated immunity. In light of these novel findings the particular role of THP as a specialized defense molecule in the urinary tract is discussed.