Tumorigenesis is a complex and multistep process involving genetic and epigenetic changes within the tumor cell, as well as supportive conditions within the tumor microenvironment (TME). The TME is widely implicated in tumorigenesis because it harbors tumor cells that interact with surrounding cells through the circulatory and lymphatic systems to influence the development and progression of cancer. Moreover, nonmalignant cells in the TME play essential roles in all stages of carcinogenesis by stimulating and facilitating uncontrolled cell proliferation. A key contributory condition is angiogenesis, blood vessel growth, which plays a critical role in the growth of cancer as solid tumors require a blood supply to grow past a few millimeters in size. Tumors promote this blood supply to form by releasing chemical signals that stimulate angiogenesis. Angiogenesis is a major point of biomedical research that has led to the clinical approval of several antiangiogenic agents resulting in new treatment strategies. This chapter outlines some of the most important aspects of the interrelationship between tumor cells and its microenvironment leading to tumor progression. The focus is on angiogenesis and incorporates novel antiangiogenic strategies and therapies.