The vascular endothelial growth factor (VEGF) family and its associated cognate receptors are critical components of angiogenesis, the process of new blood vessel formation. Under normal conditions, angiogenesis supports organism development and tissue homeostasis in a tightly controlled fashion. However, in the tumor microenvironment, several conditions, such as hypoxia and unchecked growth factor expression can lead to tumor angiogenesis, enabling endothelial proliferation and vessel assembly, which support cancer growth. Not only does tumor angiogenesis enable tumor proliferation, but its imbalance of regulators cause abnormal vascular structure, which can increase chemoresistance during therapy. Lymphangiogenesis, or the metastases-driven angiogenesis in the lymphatic system, has recently been identified as an essential process for tumor spread to lymph nodes and is driven through unique members of the VEGF signaling pathway family. Inhibition of tumor angiogenesis as an anti-cancer therapeutic strategy has resulted in the development of several recently approved drugs, unfortunately accompanied by angiogenic-related safety issues and off-target associated liabilities unique to individual drug profile. This review summarizes the role of the VEGF and VEGFR families in tumor biology and the therapies available that target these angiogenic pathways.