The single-tablet combination of vildagliptin and metformin addresses key defects of type 2 diabetes for improved glycemic control. By inhibiting the dipeptidyl peptidase-4 (DPP-4) enzyme, vildagliptin raises the levels of the active incretin hormones, glucagon-like peptide 1 and glucose-dependent insulinotropic peptide. This leads to increased synthesis and release of insulin from the pancreatic beta cells and decreased release of glucagon from the pancreatic alpha cells. The combination tablet also contains metformin, which addresses insulin resistance. The complementary mechanisms of action of the two agents in combination have been shown to provide additive and sustained reductions in hemoglobin A(1c) compared with metformin monotherapy. In active-controlled trials, the vildagliptin-metformin combination has been shown to produce equivalent reductions in hemoglobin A(1c) to pioglitazone-metformin and glimepiride-metformin combinations, without significant risk of hypoglycemia and without causing weight gain. In clinical trials, the overall incidence of any adverse event was similar in patients randomized to vildagliptin plus metformin and placebo plus metformin. Available data support the use of vildagliptin in combination with metformin as a promising second-line treatment for the management of type 2 diabetes and this is reflected in the latest UK National Institute for Health and Clinical Excellence draft guideline for consultation on new agents for blood glucose control in type 2 diabetes.