Angiogenesis is a complex process of new vessel formation on pre-existing blood vessels. It starts with functional or structural insult of the endothelium which triggers switch of quiescent endothelial cells to active angiogenic phenotype. Under physiological conditions, angiogenesis is limited in time and proliferative power of endothelial cells owing to the finely tuned balance between pro-angiogenic and anti-angiogenic programs. Stressful conditions as hypoxia rapidly disrupt this balanced state eliciting pro-angiogenic switch, and resulting in unrestricted endothelial proliferation and acceleration of angiogenesis which are crucial for tumorigenesis and development of other pathological conditions. Dipeptidyl peptidase-4 (DPP-4) is cell-surface glycoprotein which serves as serine ectopeptidase. DPP-4 plays a crucial role in the pathophysiological regulation of metabolism, immune and inflammatory responses, cancer development and cell adhesion via its catalytic and non-catalytic functions. PPP-4 inhibitors or gliptins are currently approved anti-hyperglycemic agents for type-2 diabetes mellitus. Pre-clinical studies and clinical experience have clearly acknowledged the organ-protective pleiotropic effects of DPP-4 inhibitors. Still, the literature shows conflicting results regarding the potential effects of these drugs on angiogenic processes. In this review, we will highlight the effects of DPP-4 inhibitors on different regulatory factors and conditions which control angiogenesis with specific emphasis on the most recent findings in this regard. Then, we will explore the underlying reasons and mechanisms behind the contradictory findings down to a conclusion of the ultimate effects of DPP-4 inhibitors in angiogenesis during physiological and pathological states.