Urinary tract infection (UTI) is the most common nonepidemic bacterial infection in humans, representing a constant danger for the host. Both innate and adaptive components of the immune system as well as stromal cells including bladder epithelium are involved in the prevention and clearance of UTI. However, the particular properties of the urogenital tract, which does not comprise typical physical barriers like a mucus or ciliated epithelium, necessitate soluble mediators with potent immunomodulatory capabilities. One candidate molecule capable of both mediating direct antimicrobial activity and alerting immune cells is the evolutionary conserved Tamm-Horsfall protein (THP). Tamm-Horsfall protein is exclusively produced by the kidney in the distal loop of Henle; however, its definite physiological function remains elusive. Mounting evidence indicates that beyond a mere direct antimicrobial activity, THP exerts potent immunoregulatory activity. Furthermore, the genetic ablation of the THP gene leads to severe infection and lethal pyelonephritis in an experimental model of UTI. Recent data are provided demonstrating that THP links the innate immune response with specific THP-directed cell-mediated immunity. In light of these novel findings we discuss the particular role of THP as a specialized defence molecule. We propose an integrated model of protective mechanisms against UTI where THP acts by two principle nonmutually exclusive mechanisms involving the capture of potentially dangerous microbes and the ability of this peculiar glycoprotein to induce robust protective immune responses against uropathogenic bacteria.