Bariatric surgery is the most effective available treatment for obesity. The most frequently performed operation, Roux-en-Y gastric bypass (RYGB), causes profound weight loss and ameliorates obesity-related comorbid conditions, especially type 2 diabetes mellitus (T2DM). Approximately 84% of diabetic patients experience complete remission of T2DM after undergoing RYGB, often before significant weight reduction. The rapid time course and disproportional degree of T2DM improvement after RYGB compared with equivalent weight loss from other interventions suggest surgery-specific, weight-independent effects on glucose homeostasis. Potential mechanisms underlying the direct antidiabetic impact of RYGB include enhanced nutrient stimulation of lower intestinal hormones (e.g. glucagon-like peptide-1), altered physiology from excluding ingested nutrients from the upper intestine, compromised ghrelin secretion, modulations of intestinal nutrient sensing and regulation of insulin sensitivity, and other changes yet to be fully characterized. Research aimed at determining the relative importance of these effects and identifying additional mechanisms promises not only to improve surgical design but also to identify novel targets for diabetes medications.