Dipeptidyl peptidase-4 (DPP-4) is a widely expressed enzyme that functions to cleave the two N-terminal amino acids from certain bioactive peptides. The incretin hormone, glucagon-like peptide-1 (GLP-1) is a substrate for this cleavage and this results in inactivation of the hormone. Since GLP-1 is antidiabetic due to its combined actions to stimulate insulin secretion, increase beta-cell mass and inhibit glucagon secretion, inhibition of DPP-4 has been developed as a therapy of type 2 diabetes to target the islet dysfunction in the disease. This development has been successful: in 2006, the first DPP-4 inhibitor reached the market and today several DPP-4 inhibitors exist. They are all orally active and work through a two to three-fold increase in the circulating concentration of GLP-1. DPP-4 inhibitors are safe and highly tolerable with reported incidences of adverse events being similar as in study groups with placebo. Of special interest is that the risk for hypoglycemia is low and that the treatment is weight neutral rather than being associated with risk for hypoglycemia and/or weight gain which are commonly seen for other therapies. DPP-4 inhibition is most commonly used as add-on therapy to on-going metformin therapy when metformin alone is inadequate for a sufficient glycemic control. DPP-4 inhibition is also, however, used as monotherapy in patients in whom metformin is contraindicated or intolerable, and as add-on to on-going treatment with sulfonylurea, thiazolidinediones or insulin. HbA1c is lowered by approximately 0.6-1.1% by DPP-4 inhibition, with the outcome related to baseline HbA1c. Hence, DPP-4 inhibition is now established as an efficient and highly tolerable oral treatment of type 2 diabetes.