It has been nearly 9years since the FDA (Food and Drug Administration) approved the first anti-angiogenic drug (bevacizumab) for treatment of metastatic colorectal cancer. Other angiogenic inhibitors have since been approved or are in different stages of clinical trials. However, continued clinical and preclinical investigations have identified major drawbacks associated with the application of this class of agents, including inherent/acquired resistance and induction of tumor invasiveness. In addition, lack of thoroughly validated predictive biomarkers has been one of the major hurdles to stratify cancer patients and to monitor tumor progression and response to the therapy. Investigations in clinic and preclinical models have provided some molecular and cellular mechanisms for the above challenges. This review aims to provide a concise update from recent findings.