The response of Toll-like receptor 4 (TLR4) to lipopolysaccharide (LPS) is thought vital for resisting infection. Since aberrant TLR4 signaling may initiate inflammatory conditions such as the sepsis syndrome, we sought a component of normal cells that might provide local control of TLR4 activation. We found that antibodies that block chemokine receptor 4 (CXCR4) function enhanced TLR4 signaling, while increased expression of CXCR4 or addition of the CXCR4 ligand SDF-1 suppressed TLR4 signaling induced by LPS. These findings suggest that CXCR4 could exert local control of TLR4 and suggest the possibility of new therapeutic approaches to suppression of TLR4 function.