The urinary tract is one of the most intractable mucosal surfaces for pathogens to colonize. In addition to the natural barriers at this site, potential pathogens have to contend with the vigorous local innate immune system. Several Toll-like receptors (TLRs) have been identified on epithelial cells of the bladder and the kidneys which mediate a variety of powerful immune responses. A common finding among successful uropathogens is their intrinsic ability to suppress TLR-mediated responses. As antibiotic therapy becomes increasingly ineffective, employing boosters of the innate immune system in the urinary tract may become a viable option.