Toll-like receptors (TLRs) recognize molecular patterns displayed by microorganisms, and their subsequent activation leads to the transcription of appropriate host-defense genes. Here we report the cloning and characterization of a member of the mammalian TLR family, TLR11, that displays a distinct pattern of expression in macrophages and liver, kidney, and bladder epithelial cells. Cells expressing TLR11 fail to respond to known TLR ligands but instead respond specifically to uropathogenic bacteria. Mice lacking TLR11 are highly susceptible to infection of the kidneys by uropathogenic bacteria, indicating a potentially important role for TLR11 in preventing infection of internal organs of the urogenital system.