Metastasis is the most common cause of death in cancer patients. There are two main routes by which tumor cells disseminate, through blood vessels (hematogenous spread) and through lymphatic vessels (lymphogenous spread). Angiogenesis, the acquisition of new blood vessels, is an important step in tumor progression. Tumors that cannot switch to the angiogenic phenotype remain small dormant lesions. Therefore, drugs aimed at inhibiting angiogenesis are actively being investigated. Therapies targeted against lymphangiogenesis, the growth of new lymphatic vessels, are beginning to be explored. An ideal inhibitor may be one that is anti-angiogenic as well as anti-lymphangiogenic, thereby suppressing both routes of metastasis. Members of the vascular endothelial growth factor (VEGF) family, including VEGF-A and VEGF-C, stimulate the growth of blood vessels and lymphatic vessels. A common receptor expressed on both adult blood vessels and lymphatic vessels is neuropilin 2 (NRP2). Neuropilins are cell surface receptors for members of the VEGF family as well as for members of the semphorin family of axonal guidance mediators. Recently we have demonstrated that one member of the class 3 semaphorins, Semaphorin 3F (SEMA3F), can inhibit human melanoma metastasis. Melanoma is the most lethal skin cancer with most deaths occurring from distant metastases. Phenotypically, SEMA3F-overexpressing tumors are hypo-vascular, encapsulated, and resemble benign nevi. In vitro, SEMA3F inhibits tumor cell adhesion to fibronectin by inhibiting beta 1 integrin levels, inhibits tumor cell motility, and inhibits tumor cell invasion through matrigel. In vivo, mock-transfected tumors are circumscribed with many large, open-lumened lymphatic vessels and contain intratumoral lymphatic vessels as well, while tumors overexpressing SEMA3F do not contain lymphatic vessels or have dilated surrounding lymphatics. SEMA3F may inhibit angiogenesis and lymphangiogenesis by a novel mechanism, which is the repulsion of vascular and lymphatic endothelial cells (EC) expressing NRP2 similar to the way SEMA3F repels neurons. Together these results indicate that SEMA3F is a potent metastasis inhibitor that targets both tumor and stromal cells and raise the possibility of SEMA3F having therapeutic potential.