The gastrointestinal tract is highly adapted for the digestion and absorption of long chain fat: a rich energy source. Indeed much of the machinery (delayed gastric emptying, increased surface area, bile secretion) is only truly necessary for efficient lipid handling. This process is not passive: the gut epithelium is able to sense the presence of fat, responding rapidly and appropriately. It is now clear that the key sensory cell type responsible is the enteroendocrine cell (EEC). The best exemplar for fat sensing is the CCK-secreting I-cell, principally situated in the duodenum. CCK acts as a classical hormone, but also via vagal afferent fibres. The effects of fat on the gut via CCK are highly chain length specific. We established that there is a key requirement for a chain length of C12 and longer in humans (1). Consequent differential effects on gall bladder emptying and gastric emptying can be observed, and are not seen with shorter fatty acids. This also translates into a differential effect on gastric capacity, which may have salience for satiety (2). We have begun to explore the cellular basis for the fat sensory system. The murine cell line STC-1 is the best available model, and responds in a highly similar manner to that observed in vivo (3). There is a key dependency on intracellular calcium, with evidence both for mobilisation of intracellular and extracellular pools. The signalling pathway remains elusive, although there is some evidence fatty acids may at least in part transduce their own signal (4). There is a clear need for free fatty acid to induce signalling: intact triglycerides are inert. The physicochemical properties of fat may also be important: hydrophobicity increases with increasing chain length. C12 is the first saturated fatty acid to be solid at body temperature, and appreciably less soluble in water than chains up to C10. The recent deorphanisation of GPCRs (GPR 40, 41,43,120) and reassignment as fatty acid receptors has potentially transformed this area. GPR41 and 43 are more likely to be short chain fatty acid receptors. Although the best evidence exists for GPR40 as the pancreatic beta cell fatty acid sensor, there is evidence for its expression in the gut and in EEC cell line models. Heterologous expression of GPR40 subcloned from STC-1 cells in Xenopus laevis oocytes confers fatty acid responsiveness similar to that observed in STC1 cells (5). However, the current lack of a specific antibody and of techniques to isolate EEC has hampered confirmation of this as the primary EEC lipid sensor. Other cell types have been postulated to play a role in fatty aid sensing including the enterocyte via apolipoprotein A-IV, and the brush cell population. It is unclear whether submucosal sensory nerves have an independent fat sensing capability: this seems more likely to be the case for short chain fatty acids. Given the central role of EEC in fat sensing it is now essential to develop models to study primary cell physiology in health and disease. There is now evidence that EEC hyperfunctionality is implicated in the reduction in food intake observed in intestinal inflammation. Mimickry of these mechanisms in the absence of fat would therefore have potential applications in the control of food intake, and perhaps in the gastrointestinal handling of oral drugs.