Vascular endothelial growth factor (VEGF) plays a central role in angiogenesis. A number of studies have focused on its role in health and disease and discussed the possibility of VEGF as both a therapeutic tool and target based on its specific actions on vascular proliferation and cell survival. On one side, anti-VEGF therapies are at the fore-front of treatment of many solid tumors, but blockade of VEGF carries collateral effects such as hypertension and renal damage largely due to abnormalities in the microvasculature. On the other hand, recent clinical and experimental evidence has shown the feasibility of using VEGF administration to protect ischemic tissues such as the myocardium or the kidney via stimulation of microvascular proliferation and repair. In this commentary, we discuss the possibility and potential mechanisms of using intra-renal administration of VEGF to preserve the renal microcirculation and, consequently, decrease progressive renal injury in chronic renovascular disease. Targeted administration of VEGF may constitute a novel stand-alone or co-adjuvant intervention with the potential to become a part of a comprehensive plan to protect renal function.