Infection of the urinary tract remains one of the most common infections affecting mankind. Renal epithelial cells, being one of the first cells to come into contact with invading organisms, are in a key position to coordinate host defense. The epithelium not only provides a physical barrier to infection, but can also augment the immune response via the production of a number of inflammatory mediators and antimicrobial proteins. Recent work has demonstrated that cells of the innate immune system, including epithelial cells, express toll-like receptors (TLRs), with the capacity to recognize bacterial components. Although the exact mechanisms remain unclear, engagement of TLRs can lead to epithelial cell activation and the production of inflammatory mediators. These include complement proteins, other bactericidal peptides, and chemotactic cytokines. The resulting inflammatory infiltrate serves to aid bacterial clearance, but can also lead to renal damage. In this review, we describe how renal epithelial cells contribute to the innate immune response to ascending urinary tract infection. We specifically relate previous work to more recent developments in this field. An improved understanding of the mechanisms involved may highlight potential therapeutic avenues to aid bacterial clearance and prevent the renal scarring associated with infection.