Anti-angiogenic therapy with bevacizumab along with chemotherapy is a useful and approved regimen in the U.S.; however, most tumors rapidly adapt and develop resistance to such drugs. To understand the underlying mechanisms, we have established in vitro and in vivo model systems of adaptive resistance to anti-VEGF therapy. Our preliminary data suggest that epigenetic changes in the tumor microenvironment play a significant role in such resistance. Importantly, our data suggest that resistance to anti-VEGF therapy can be reversed by demethylating agents. To our knowledge, the proposed work is the first to combine epigenetic analysis of human ovarian cancer samples with biological studies that combine demethylation agents with bevacizumab. This study may allow us to identify the predictive markers for response to anti-VEGF therapies and demonstrate the potential use of demethylating drugs for reversing resistance to anti-angiogenesis therapies. Concurrently, our results may help us to improve the use the anti-VEGF treatment in cancer patients by finding the right combination.