Lipopolysaccharide (LPS) is the principal initiator of septic shock and it is to a large extent responsible for post-operative mortality. The use of antibiotics is still the most successful therapy against infection that may lead to sepsis and septic shock. With the advent of antibiotic resistant strains like MRSA the usefulness of conventional antibiotics is declining and new treatment strategies for LPS-mediated septic shock are called for. In this review we discuss the molecular mechanisms that are involved in the recognition of LPS and in the initiation of an immune response. Furthermore, we also review the recent insights in the signal transduction including receptor clustering and signalosome activation. Further insight into LPS-dependent signal transduction will assist the development of novel rational therapy.