The landmark discovery by Bayliss and Starling in 1902 of the first hormone, secretin, was based in part on the observation that a response (pancreatic secretion) following a stimulus (intestinal acidification) occurred after section of the relevant afferent nerve pathway. With the subsequent discovery of many more hormones, numerous examples of interactions between endocrine and autonomic efferent pathways emerged. But it was to be nearly 80 years before it was discovered that visceral afferent neurons could themselves also be targets for gut and other hormones. Signalling from gut to brain by gut hormones acting on vagal afferent neurons is now recognised to be an early step in the activation of vago-vagal reflexes regulating gastric acid secretion and in controlling nutrient delivery to the intestine by modulating gastric emptying. Importantly, gut hormones acting on vagal afferent neurons also influence food intake and interest in these mechanisms has grown rapidly in view of the alarming global increase in obesity. Several of the gut hormones released by nutrients (cholecystokinin, CCK; PYY3-36; glucagon-like peptide-1, GLP-1) excite vagal afferent neurons to activate an ascending pathway via the brainstem and hypothalamus leading to inhibition of food intake. Conversely others eg ghrelin, that are released in the inter-digestive period, inhibit vagal afferent neurons leading to increased food intake. Moreover, the vagal afferent neurons targeted by gut hormones are now emerging as integrators of several different types of peripheral signal. Thus, (a) leptin stimulates these neurons and potentiates the effects of CCK indicating mechanisms that integrate adipose- and gut-derived signals. (b) Nutrient status determines the neurochemical phenotype of vagal afferent neurons and in particular regulates a switch between states that emphasise orexigenic or anorexigenic signalling; for example food withdrawal increases the expression of receptors (eg cannabinoid, CB1, receptor) and a putative neuropeptide transmitter (melanin concentrating hormone, MCH) that are associated with stimulation of food intake, while refeeding increases the expression of a receptor (Y2) and neuropeptide transmitter (cocaine and amphetamine regulated transcript, CART) associated with satiety signalling. (c) The gut luminal and tissue environments modulate vagal sensitivity to gut hormones through mechanisms that vary with different regions of the gut. Thus small intestinal infection, and proinflammatory cytokines, potentiate vagal afferent responses to CCK leading to loss of appetite; in the stomach, however, infection and inflammation can be regarded as physiological states, and here expression of plasminogen activator inhibitor (PAI)-1 is increased by inflammation and depresses vagal afferent sensitivity to CCK, thereby protecting nutrient intake. Finally, (d) shifts in the gut microbiota that occur in obesity are associated with leptin insensitivity in vagal afferent neurons, and therefore insensitivity to CCK as well, which appears to develop before leptin-insensitivity in hypothalamic neurons. Together these observations indicate a hitherto unsuspected level of sophistication in the signalling between gut to brain that underlies homeostatic mechanisms controlling nutrient intake. They also suggest new opportunities to develop treatments for obesity and feeding disorders.