Sepsis, the systemic inflammatory response to infection, is considered the major cause of death among critically ill patients in the developed world. While there is a general view that this reflects contributions from both the pathogen and the host with respect to an inappropriate inflammatory response, there is a lack of agreement as to the key immune mechanisms. This has been reflected in the diverse range of immunotherapies tested in clinical trials, often with rather marginal effects. The case has been made for a pathogenic role of excessive immunity, the so‐called ‘cytokine storm’, and for a role of too little immunity through immune paralysis. Apoptosis is implicated as a key mechanism in both this immune paralysis and the multi‐organ failure that is a feature of severe sepsis. A number of polymorphisms have been implicated in susceptibility to sepsis, including cytokine genes, HLA class II and caspase‐12. In this review we focus in particular on the role of group A streptococci in severe sepsis. Here the effect of bacterial superantigens appears to be a correlate of inflammatory activation, although the precise evolutionary role of the superantigens remains unclear. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.