Metastasis to regional lymph nodes is probably the most common route for cancer spread. Unlike blood-stream metastasis, the mechanism that underlies lymphatic metastasis is relatively poorly understood. We are studying the complex interplay between various growth factors and cytokines in the tumor microenvironment that contributes to tumor lymphangiogenesis and lymphatic metastasis. We have recently discovered several novel lymphangiogenic factors that significantly promote intra- and peri-tumoral lymphangiogenesis, leading to widespread lymph node metastasis. Notably, these factors could coordinately stimulate lymphangiogenesis by regulation of distinctive steps of this complex process.  For example, FGF-2 and VEGF-C synergistically induce lymphangiogenesis by promoting lymphatic endothelial cell proliferation and the tip formation, respectively. Another recent example is the synergistic lymphangiogenesis activity by TNF-α and VEGF-C. These findings not only uncover the complex mechanism underlying tumor lymphangiogenesis but also provide important information for development of new cancer drugs that target tumor lymphangiogenesis.