Lymphatic endothelial cells (LECs) originally differentiated from venous endothelial cells express several specific makers that distinguish them from the blood vessels. Lymphangiogenesis, a complex process of sprouting of new lymphatic vessels, is regulated by multiple direct and indirect growth factors. Vascular endothelial growth factor-C (VEGF-C) is the most potent and selective lymphangiogenic factor that plays a crucial role in the establishment of the first lymphatic vessel during embryonic development and in mediating lymphatic metastasis. In addition to VEGF-C, recent studies show that a range of known tumor-produced angiogenic factors also stimulates lymphangiogenesis, suggesting complex and tight regulations of this process. These tumor-derived lymphangiogenic factors may either alone or jointly promote lymphatic metastasis. Understanding regulatory mechanisms of lymphangiogenesis is pivotal for development of lymphangiogenesis antagonists that might therapeutically be used for intervention of lymphatic metastasis.