Angiogenesis is a prerequisite for the growth and metastasis of solid tumors. Studies have confirmed that in the absence of angiogenesis, tumors rarely have the ability to develop beyond a few millimeters in diameter. Tumor-associated endothelium is activated by the production of soluble factors by tumor and stromal cells. Tumor-associated endothelial cells are physiologically homogeneous and divide more frequently. Thus, targeting the proliferation of tumor neovasculature will form an effective anti-cancer therapy. With the identification of drug and biological molecules that inhibit the growth of tumor endothelium, several attempts have been made in preclinical and clinical research to evaluate the potential of anti-angiogenic therapy. Although several drugs and purified proteins have shown promise, their wide-spread application is limited by half-life, side effects and cost involved. Gene therapy approaches, on the other hand, have the potential to overcome these limitations. Further, genetic transfer of anti-angiogenic genes can be combined with other treatments including radiation therapy or chemotherapy for synergistic effects. In this review, we provide a comprehensive account of factors and mechanisms underlying tumor angiogenesis, the potential and limitations of available gene therapy vectors for anti-angiogenesis and current status of preclinical and clinical gene therapy studies targeting tumor angiogenesis.