Sepsis is a very heterogeneous clinical syndrome broadly defined as the systemic host response to an infection. Until very recently, the prevailing concept of the pathogenesis of sepsis was that mortality is the consequence of an uncontrolled hyperinf lammatory response of the host. The disappointing results of nearly 40 years of anti-inflammatory strategies and the development of animal models that more closely mimic clinical sepsis have led to the reconsideration of the pathophysiology of sepsis. Sepsis is now considered a misbalance between proinflammatory reactions (designed to kill invading pathogens but at the same time responsible for tissue damage) and anti-inflammatory responses (designed to limit excessive inflammation, but at the same time making the host more vulnerable for secondary infections). This review discusses key components of the pro- and anti-inflammatory response to sepsis, listing potential novel interventional strategies along the way.