Angiogenesis, the formation of new blood vessels, is a normal physiological process during embryonic development and wound healing but can be pathological during certain conditions like tumor growth. The angiogenic process is stimulated in growing tumors by several transcriptional factors and signaling pathways, involving various types of cells especially endothelial cells. Physiological angiogenesis is controlled by the balance between pro-angiogenic factors and anti-angiogenic factors. The balance between pro-angiogenic factors and anti-angiogenic factors is important for controlled physiological angiogenesis. However, imbalance between these factors with overactivity of the angiogenic stimulants provokes the “angiogenic switch” for cancer neovascularization leading to enhanced tumor growth, invasion and metastasis. The tumor blood vessels are usually malformed, heterogeneous, and variable in number and sizes according to the type of cancer and location of vessels within the tumor. Targeting tumor angiogenesis by blocking the expression or activity of proangiogenic factors has been demonstrated to suppress tumor growth in many preclinical studies with possible anticancer clinical relevance. Inhibitors of angiogenesis such as monoclonal antibodies or tyrosine kinase inhibitors have shown promising effectiveness in treatment of various types of cancer. However, the clinical outcome of these therapeutic agents has been modest, sometimes disappointing, and associated with significant toxicities. The aim of this chapter would be to discuss the molecular mechanisms of angiogenesis and its role in tumor progression and spread, to explain the rational for use of angiogenesis inhibitors in cancer therapy. This chapter also focuses on classification of anti-angiogenic agents in combination with other anticancer modalities for treatment of malignant diseases. Furthermore, extensive investigation of the synergistic combinations of anti-angiogenic agents and their diverse cellular targets could provide effective strategies for future treatment of cancer.