Sitagliptin is a once-daily, orally active, competitive and fully reversible inhibitor of dipeptidyl peptidase 4, the enzyme that is responsible for the rapid degradation of the incretin hormone glucagon-like peptide-1. It is the first in this new class of antihyperglycaemic agents to gain regulatory approval for the treatment of Type 2 diabetes, both as a monotherapy and for use in combination with metformin or a thiazolidinedione. In clinical trials of < or = 1-year duration, sitagliptin improves glycaemic control by reducing both fasting and postprandial glucose concentrations, leading to clinically meaningful reductions in glycosylated haemoglobin levels. It is safe and well tolerated, with a side-effect profile that is similar to that of the placebo, a low incidence of hypoglycaemia and body weight neutrality. Further clinical experience with sitagliptin will reveal its long-term durability, safety and efficacy.