In normal epithelial cells, there is a balance of pro- and antiangiogenic and lymphangiogenic factors maintaining proper tissue homeostasis. During malignant transformation, early loss of one such factor, the lymphatic endothelial cell inhibitor SEMA3F, is necessary to enable pathologic lymphangiogenesis. As the squamous cell carcinoma cells develop a more aggressive phenotype, acquired expression of surface receptors like neuropilin 2 (NRP2), a receptor typically expressed at high levels on lymphatic endothelial cells, further facilitate tumor vascularity, expansion, and metastatic spread. Thus, expression of SEMA3F may function in both an autocrine and paracrine fashion through NRP2 to inhibit tumor growth, lymphatic invasion, and metastasis. For details, see article by Doçi and colleagues on page 2937.