The stimulation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) induces the release of critical proinflammatory cytokines that are necessary to activate potent immune responses. LPS/TLR4 signaling has been intensively studied in the past few years. Here we review molecules involved in TLR4-mediated signaling, including players that are involved in the negative regulation of this important pathway.