Lipopolysaccharide (LPS) of gram-negative bacteria is capable of activating the immune system of higher animals, which may lead to cytokine-induced lethal shock and death. LPS has little toxicity for the frog and fish, but it kills the horseshoe crab instantly by causing intravascular blood coagulation. The response to LPS evolved from simple reactions in lower animals into an intense reaction in mammals that involves a massive immune activation leading to a profound neuroendocrine and metabolic response. This is now known as the acute-phase response (APR). During APR, LPS-binding proteins (LBP) are produced by the liver in rapidly increasing quantities under the influence of interleukin-6, glucocorticoids, and catecholamines. After combination with LPS, LPB is capable of activating monocyte-macrophages and granulocytes via the CD14 surface receptor. Other receptors (CD18, 80-kDa receptor) allow for direct action by LPS of phagocytes, B and T lymphocytes, and other cells. Numerous other acute-phase proteins are produced in the liver, including C-reactive protein, complement components, fibrinogen, enzyme inhibitors, and anti-inflammatory proteins. Similar responses may be stimulated by subtoxic doses of LPS or by detoxified LPS, which manifest in endotoxin tolerance. Tolerant animals and man show increased resistance to LPS, to infections, and to various noxious insults. Infection and various forms of tissue injury are also capable of causing APR. There is much evidence to indicate that APR, which manifests in febrile illness, is an efficient host defense reaction. It is an emergency response in cases where specific immunity fails to protect the host. Therefore, the neuroimmunoregulatory network converts the immune system to a less specific, but rapid and more efficient response, APR. The hypothesis is presented that intestinal LPS serves to amplify the APR in response to various insults, which contribute to host defense, regeneration, and healing.