Lipopolysaccharide (LPS), which is derived from the cell wall of gram-negative and some gram-positive bacteria, plays a major role is the pathogenesis of septic shock. Initiation of these responses depends on LPS interaction with a number of immune cells, not least the mononuclear phagocyte (MP). Mononuclear phagocytes bind the LPS/lipopolysaccharide-binding protein complex through the CD14 receptor and thus mediate the release of a wide range of inflammatory mediators. Release of these mediators is teleologically beneficial but under certain circumstances may be detrimental, resulting in the systemic inflammatory response syndrome. The development of this syndrome is not clearly understood but appears, in part, to be dependent on the ability of the host to respond to these mediators. This review evaluates the mechanisms of LPS-MP interaction and the therapeutic strategies aimed at inhibiting this interaction.