Endotoxin tolerance is a well known phenomenon, described both in vivo and in vitro, in which repeated exposure to endotoxin results in a diminished response, usually characterised as a reduction in proinflammatory cytokine release. The mechanisms responsible for endotoxin tolerance have become clear in recent years as our understanding of the pathways through which endotoxin mediates its effects has increased. The principal cell surface receptor for the lipopolysaccharide (LPS) component of endotoxin is Toll-Like Receptor 4 (TLR-4), a member of a highly conserved family of receptors specific for highly conserved bacterial and viral components which play key roles in the early inflammatory response to pathogens. As our understanding of the part played by TLR-4 signalling in endotoxin has increased, so it has become clear that response tolerance occurs to other TLR ligands in addition to LPS/endotoxin. Clinically, endotoxin/TLR response tolerance is thought to play an important part in susceptibility to reinfection in patients treated for severe sepsis. Whilst this may have developed as a protective evolutionary mechanism to prevent death caused by overwhelming cytokine release in sepsis, in the modern era of antibiotics, vasopressors and organ support, undoing this downregulation or re-booting the immune system may be a useful therapeutic target in the postseptic patient. This should, however, be approached with caution as it is possible that endotoxin/TLR response tolerance is also a physiological regulatory mechanism in areas normally exposed to bacterial-derived TLRligands such as the gut and liver.