Sepsis is a major health problem. The concept that sepsis mortality is the result of an uncontrolled hyperinflammatory host response has recently been challenged. It is now widely thought that the host response to sepsis involves many, concomitant, integrated, and often antagonistic processes that involve both exaggerated inflammation and immune suppression. Several novel mediators and pathways have been shown to play a part. Moreover, evidence is accumulating that microbial virulence and bacterial load contribute to the host response and the outcome of severe infections. A complex and dynamic interaction exists between pathogens and host immune-defence mechanisms during the course of invasive infection. Some pathogens have acquired the capacity to communicate with each other and sense the host's vulnerabilities. Bidirectional signals are detectable at the critical interface between the host and microbial invaders. The outcome of this interaction determines the fate of the host at the outset of the septic process. A formidable array of innate and acquired immune defences must be breached if a pathogen is to successfully disseminate and cause severe sepsis and septic shock. This Review summarises current knowledge of microbial pathogenesis and host-pathogen interactions during sepsis and the ensuing development of potential therapeutics.