Semaphorin 3E (Sema3E), previously known as SemaH, is one of six Class 3 (secreted) semaphorins which function in axon guidance and/or vascular tip cell guidance during development (1). Sema3E contains a seven-blade beta -propeller sema domain, a cysteine-knot PSI domain, an Ig-like domain, and a basic region. Dimerization and cleavage within the basic region are required for the repulsing activity of class 3 semaphorins (2). Sema3E can also be cleaved at a furin consensus sequence C-terminal to the sema domain, resulting in a 61 kDa form that does not dimerize and is highly expressed in tumor cell lines with metastatic potential (3, 4). Mature human Sema3E shares 90% aa sequence identity with mouse and rat Sema3E. Alternative splicing generates a short isoform that lacks the signal peptide and the N-terminal 35 residues of the mature protein. Sema3E signaling is transduced by Plexin D1 which may also be associated with Neuropilin 1 and/or VEGF R2 (2, 5, 6). Its interaction with Plexin D1 inhibits axon migration in the neocortex and forebrain (6, 7), although it can attract axons that express both Plexin D1 and Neuropilin 1 (6). Sema3E promotes axonal growth (5), the development of glutamatergic synaptic specificity (8, 9), and the development of GnRH producing neurons (10). Genetic disruption of either Sema3E or Plexin D1 in mouse causes excessive and disorganized vascular growth and branching, indicating the importance of this ligand-receptor pair for vascular guidance (11, 12). In addition, Sema3E is up-regulated by inflammatory macrophages and damaged hepatocytes (13-15). It inhibits smooth muscle cell proliferation and migration in the asthmatic airway (16), promotes hepatic stellate cell activation and wound healing (15), and regulates the migration of developing thymocytes (17).