Roux-en-Y gastric bypass surgery (GBP) results in 30–40% sustained weight loss and improved type 2 diabetes in up to 80% of patients. The relative contribution of the gut neuroendocrine changes after GBP versus the weight loss has not been fully elucidated. There are clear differences between weight loss by GBP and by dietary intervention or gastric banding. One of them is the enhanced post-prandial release of incretin hormones and the recovery of the incretin effect on insulin secretion after GBP, not seen after diet-induced weight loss. The favorable changes in incretin hormones after GBP result in recovery of the early phase insulin secretion and lower post-prandial glucose levels during oral glucose administration. The enhanced incretin response may be related to the neuroglycopenia post-GBP. In parallel with changes of glucose metabolism, a larger decrease of circulating branched-chain amino acids in relation to improved insulin sensitivity and insulin secretion is observed after GBP compared to diet. The mechanisms of the rapid and longterm endocrine and metabolic changes after GBP are not fully elucidated. Changes in rate of eating, gastric emptying, nutrient absorption and sensing, bile acid metabolism, and microbiota may all be important. Understanding the mechanisms by which incretin release is exaggerated post-prandially after GBP may help develop new less invasive treatment options for obesity and diabetes. Equally important would be to identify biological predictors of success or failure and to understand the mechanisms of weight regain and/or diabetes relapse.