Leukocytes have a fundamental role in innate and adaptive immunity, wound healing, tumour surveillance and in tissue remodelling. It is their function in the inflammatory response however that is of most interest to us in the intensive care setting. Over the last three decades we have gained significant insights into leukocyte activation, recruitment and mediator secretion and the contribution of these agents to both the onset and resolution of sepsis and inflammation. The body relies on the inflammatory response for protection. Leukocytes occupy a pivotal position in this but to maintain these cells in a state of permanent activation would be unsustainable, with widespread microvascular plugging, uncontrolled free radical release and an excessive metabolic demand. Leukocytes thus circulate in a quiescent state and are rapidly activated by invading pathogens and other stimuli. A direct consequence of this protective strategy is that the inflammatory response may be inadequate, with the risk of overwhelming sepsis, or excessive, leading to rampant systemic inflammation and consequent multiple organ damage. It is now becoming apparent however that in addition to leukocytes other cells have important roles both in defence against invading pathogens and in driving malignant inflammation. This review will focus on two new facets of the innate immune system, the Toll family of proteins as the signal transduction element for endotoxin, and the antimicrobial peptides. These exemplify potential damaging and protective response elements but importantly neither are restricted to leukocytes. The capacity of cells and tissues other than the leukocytes to participate and even lead in the inflammatory responses will also be explored.