TLRs activate a potent immunostimulatory response which needs to be tightly controlled. TLRs homo o heterodimerize upon ligand binding whereas TLR4 and TLR9 homodimerize (6) . TLR signaling involves a family of adaptor proteins which recruit downstream protein kinases which activate transcription factors such as nuclear factor-kB (NF-κB) and members of the interferon (IFN)-regulatory factor (IRF) family (10) . LPS signaling involves the binding of the LPS-binding protein (LBP) to LPS; this interaction leads to a disruption of LPS aggregates (10) (Fig. 2 LPS signaling, modified from (10) with permission). Upon ligand binding there is the formation of a TLR4 complex with CD14. CD14 was the first molecule shown to enhance LPS signals (17) . Interestingly TLR4 does not require CD14 to trigger epithelial signaling to uropathogenic E. coli since bladder cells do not express CD14 (18) . In addition a small molecule, myeloid differentiation 2 receptor (MD-2), participates in this complex by associating with the TLR4 extracellular domain (19) .