Angiogenesis, the growth of new vessels from pre-existing ones, is an important feature of tumor growth that has been exploited as a therapeutic target in oncology. Given its key role in facilitating blood vessel sprouting, VEGF has been a major focus of anti-angiogenic strategies, but the observation of resistance in some clinical trials utilizing such agents has led to a search for new or complementary targets in angiogenesis process. The Angiopoietin/Tie2 pathway and in particular the Angiopoietin-2 (Ang-2) ligand which is critically involved in the destabilization of normal vasculature, has been identified as one such target. The current study investigated the potential benefits of combining an Ang-2 targeted therapy with small molecule VEGF targeted agents (Sunitinib, Cediranib) in a human renal cell carcinoma model. The results showed that while both Ang-2 and VEGF interference on their own impaired tumor growth and new blood vessel formation, the combination of agents that targeted both pathways resulted in significantly superior anti-tumor and anti-angiogenic effects.