Stimulus-secretion coupling in the enteroendocrine L cell leads to release of the proglucagon-derived peptides, glucagon-like peptide-1 (GLP-1), GLP-2 and oxyntomodulin, as well as of peptide YY. These biologically-active peptides play diverse roles in the physiological response to nutrient ingestion, including regulation of glycemia, satiety and intestinal function. Although stimulated by a diversity of ingested nutrients, the L cell is notably sensitive to fatty acids, with a marked specificity for long-chain monounsaturated fats such as oleic acid. Consistent with these findings, diets that are rich in oleic acid, such as the Mediterranean diet, increase circulating levels of GLP-1 in association with improved glycemic control, in both rodents and humans. Recent studies have now begun to elucidate the mechanism of action of fatty acids on the intestinal L cell, with a number of different signaling pathways acids now being implicated, including the Galpha q-linked G protein-coupled receptors, GPR40 and GPR120, the Galpha s-coupled receptor, GPR119, and the intracellular enzyme, protein kinase Czeta. Expression of a variety of different fatty acid transport proteins, as well as of the bile acid receptor, TGR5, further illustrates the complexity of the intestinal L cell response to ingestion of fat. Collectively, these findings have piqued interest in potential therapeutic applications for L cell secretagogues. Notwithstanding, the large number of biologically-active peptides produced by the L cell must be taken into account in any such considerations.