The vascular endothelial growth factor (VEGF) family has been proposed to be the most important signaling protein family in vessel formation and maturation. VEGF receptor-2 (VEGFR-2) plays an abundant role in the most common forms of cancer. The localization of VEGFR-2 expression is important in cancer pathogenesis; however, so far, little attention has been paid to this phenomenon. Induced cytoplasmic VEGFR-2 transition from the nucleus is associated with poor prognostic cancer stages. Current VEGFR-2-targeted therapy approaches are effective in inhibiting or arresting tumor growth. Moreover, VEGFR-2-targeted therapy was demonstrated to restore the abnormal vasculature in tumors, enhancing their susceptibility toward conventional therapy. Most effects can be found when VEGFR-2-targeted therapy inhibits not only the induced angiogenesis but also the cancer cells that sometimes overexpress VEGFR-2. Nevertheless, we still have little knowledge about the mechanisms that regulate VEGFR-2 expression and how its localization is exactly involved in cancer prognosis. Further research and evaluation of VEGFR-2 regulation and its nuclear transition is necessary to develop more accurate therapeutic strategies to improve the patients' quality of life and their survival.