Abstract: Hypoxia results from long-term anti-angiogenic therapy and can stimulate hypoxia-inducible factors (HIFs). HIF-induced hy -poxia signaling is involved in various steps in tumor invasive-metastatic cascade. On the one hand, HIFs regulate epithelial-mesenchy-mal transition. On the other hand, the characteristics of pericytes around vessels and the links among endothelial cells can change; thus, tumor cells can more easily intravasate into blood vessels, survive in peripheral blood, and then reach specific organs, ultimately resulting in metastasis. This review discusses the emerging mechanisms of long- term anti- angiogenic therapy and the occurrence of metastasis.