The most widely used pharmacological therapies for obesity and weight management are based on inhibition of gastrointestinal lipases, resulting in a reduced energy yield of ingested foods by reducing dietary lipid absorption. Colipase-dependent pancreatic lipase is believed to be the major gastrointestinal enzyme involved in catalysis of lipid ester bonds. There is scant literature on the action of pancreatic lipase under the range of physiological conditions that occur within the human small intestine, and the literature that does exist is often contradictory. Due to the importance of pancreatic lipase activity to nutrition and weight management, the present review aims to assess the current body of knowledge with regards to the physiology behind the action of this unique gastrointestinal enzyme system. Existing data would suggest that pancreatic lipase activity is affected by intestinal pH, the presence of colipase and bile salts, but not by the physiological range of Ca ion concentration (as is commonly assumed). The control of secretion of pancreatic lipase and its associated factors appears to be driven by gastrointestinal luminal content, particularly the presence of acid or digested proteins and fats in the duodenal lumen. Secretion of colipase, bile acids and pancreatic lipase is driven by cholecystokinin and secretin release.