In the United States, >750,000 patients annually are thought to be at high risk for developing septic shock, with mortality rates reaching 60%. Thus, huge societal and financial costs are associated with this syndrome. Because of the high incidence and poor prognosis of septic shock, basic research has focused on the innate immune system for >2 decades. The pathophysiology of severe sepsis/shock is exceedingly complex, but there is little doubt that infection often progresses from systemic inflammatory response to severe sepsis and shock. Infection is the primary event in this sequence. There is evidence that the severity of the systemic reaction to infection (severe sepsis) is strongly influenced by the intensity of the inflammatory process at the infection sites. Efforts to understand the molecular mechanisms involved in recognition of bacterial products by members of the Toll-like receptor family are described, as well as some events that occur after receptor ligand binding that lead to new gene activation.