The incidence of sepsis is increasing worldwide, yet the mortality rate has barely decreased during the past decades and remains unacceptably high at between 20% - 40%. New knowledge on host-pathogen interactions has greatly increased our insights in the pathogenesis of sepsis. It is now clear that sepsis is not only characterized by proinflammation but also by immunosuppression. Here we give an overview of the functional interactions between bacteria and our immune system. Microbial virulence factors, pathogen recognition receptors, activation of coagulation, apoptosis and a wide range of new mediators of sepsis play a role in these interactions. Implementation of evidence-based guidelines for the rapid diagnosis and adequate treatment of sepsis has been shown to be instrumental in improving survival in sepsis. The increasing insights into the pathogenesis of sepsis have identified a whole new range of potential drugs which are currently being tested in clinical trials.