In addition to progressive pancreatic β-cell failure resulting in impaired insulin secretion, and increased insulin resistance in muscle and liver, incretin hormone-related abnormalities have been identified as key underlying defects in patients with type 2 diabetes mellitus. Treatment goals for patients with type 2 diabetes should be aligned with the basic defects of the disease. Many of the available antidiabetes agents correct hyperglycemia but do not impact other cardiovascular risk factors, and may actually aggravate some. This paper reviews the role of defects in the incretin system in the pathophysiology of type 2 diabetes, and discusses recent advances in the use of incretinbased agents that target the fundamental disease mechanisms of type 2 diabetes. The incretinbased agents reduce hyperglycemia and provide beneficial effects on surrogate markers of cardiovascular risk, including weight gain, elevated blood pressure, and dyslipidemia.