The dipeptidyl peptidase-IV (DPP-IV) inhibitors, also known as gliptins, are widely used in clinical practice either as monotherapy or in combination with other agents for the management of type 2 diabetes mellitus (T2DM). The gliptins are effective, safe, well tolerated, and conveniently administered once/day. Moreover, these agents have a low risk for drug interactions and do not require initial dosage titrations to lessen adverse effects. They are not only clinically desirable, having the most favorable side-effect profile of all available antihyperglycemic medications, but they can also be used in any stage of renal or hepatic impairment. The antihyperglycemic effects of gliptins are attributed to inhibition of the DPP-IV enzyme, thereby prolonging the half-life (t1/2 ) of incretin hormones (substrates) to promote glucose-stimulated insulin secretion. Beyond their glucose-lowering effects, gliptins may also reduce the risk of cardiovascular disease by improving endothelial function, lowering blood pressure, reducing inflammation, and delaying the progression of atherosclerosis. Although the vascular protective effects of gliptins depend on incretins, the contributions of other biologically important endogenous vasoactive substrates of DPP-IV are worthy of consideration from a therapeutic standpoint. Future and ongoing studies should help determine whether these vascular protective effects contribute to improved cardiovascular outcomes in patients with T2DM. The experimental and clinical evidence supporting the vascular protective effects of gliptins is reviewed.