Bevacizumab (BV) was associated with a survival benefit when combined with chemotherapy in metastatic colorectal cancer (mCRC). Patients who received BV plus standard chemotherapy (FOLFOX/XELOX or FOLFIRI/XELIRI) as the initial treatment of mCRC and were then continued on BV with a different chemotherapy regimen as a second-line agent after their cancer progressed lived significantly longer than patients who received chemotherapy alone in the second-line setting, based on the recent results of the ML18147 study. This is the first trial to confirm the efficacy of continuing on a BV-based regimen after disease progression and to prove the necessity of BV continuation for blocking VEGF. Aflibercept, which is a soluble fusion protein consisting of the extracellular domains of human VEGFR-1,2 linked to a human IgG1 Fc portion, binds all VEGF-A isoforms, VEGF-B, and PlGF. Regorafenib is an oral multi-kinase inhibitor that targets VEGFR, PDGFR and KIT kinases. Both drugs showed survival benefit in other phase III trials. Understanding the underlying mechanisms of resistance to anti-angiogenic therapy will facilitate the optimization of the use of these three active agents in the treatment of mCRC. The global phase III AVAGAST trial did not demonstrate a survival benefit of BV when it was administered with a chemotherapy regimen of capecitabine plus cisplatin (XP) for metastatic gastric cancer. Low tumor neuropilin-1 expression was associated with shorter overall survival (OS) in placebo-treated patients. The addition of BV seems to produce a survival benefit; patients with low tumor neuropilin-1 expression had OS treatment hazard ratio values that were better than those with high neuropilin-1 expression. A similar effect was observed in the NO16966 mCRC study (FOLFOX/XELOX ± BV). In addition, lower baseline plasma VEGF-A was correlated with longer OS. Additional data from the AVAGAST trial revealed different survival outcomes based on the histological and regional subtype of gastric cancer. Although European patients with diffuse type and distal non-diffuse type gastric cancer had the worst prognosis for survival; these individuals were most likely to benefit from the addition of BV to XP. Different approaches to the development of novel agents for each histologic type of gastric cancer treatment are required.