Class 3 semaphorins (SEMA3) were first identified as glycoproteins that negatively mediate neuronal guidance bybinding to neuropilin and repelling neurons awayfrom the source of SEMA3. However, studies have shown that SEMA3s are also secreted by other cell types, including tumor cells, where theypl ayan inhibitoryrole in tumor growth and angiogenesis (specificallySEMA3B and SEMA3F). SEMA3s primarilyinhibit the cell motilityand migration of tumor and endothelial cells byinducing collapse of the actin cytoskeleton via neuropilins and plexins. Besides binding to SEMA3s, neuropilin also binds the protumorigenic and proangiogenic ligand vascular endothelial growth factor (VEGF). Although some studies attribute the antitumorigenic and antiangiogenic properties of SEMA3s to competition between SEMA3s and VEGF for binding to neuropilin receptors, several others have shown that SEMA3s displaygrowthinhibitoryactivity independent of competition with VEGF. A better understanding of these molecular interactions and the role and signaling of SEMA3s in tumor biologywill help determine whether SEMA3s represent potential therapeutic agents. Herein, we brieflyreview (a) the role of SEMA3s in mediating tumor growth, (b) the SEMA3 receptors neuropilins and plexins, and (c) the potential competition between SEMA3s and VEGF family members for neuropilin binding. © 2009 American Association for Cancer Research.