Infusions of lipids into the small intestine potently suppress ongoing feeding. Prior work has identified potential roles for gut extrinsic vagal and non-vagal sensory innervation in mediating the ability of gut lipid infusions to reduce food intake, but the local biochemical processes underlying gut lipid sensing at the level of the small intestine remain unclear. This manuscript will summarize recent progress in the identification and characterization of several candidate gut lipid sensing molecules important in the negative feedback control of ingestion, including the fatty acid translocase CD36, peroxisome proliferator-activated receptor alpha (PPAR-α), and the fatty acid ethanolamide oleoylethanolamide (OEA). In addition, this manuscript addresses a larger role for gut lipid sensing in the overall control of energy availability by modulating not only food intake but also hepatic glucose production.