Semaphorin 4D (Sema 4D/CD100) is an axon guidance molecule with two disulfide-linked 150-kDa subunits. SEMA4D is structurally defined by a conserved 500-amino acid extracellular domain with 16 cysteines (sema domain) and also an Ig-like domain C-terminal to the sema domain. Sema4D is expressed on the cell surface as a homodimer; cysteine 679 within the sema domain is required for this dimerization.The main receptors for Sema4D are plexin-B1 and CD72. The activation of plexins by semaphorins initiates a variety of signaling processes that involve several small GTPases of the Ras and Rho families. Sema4D-Plexin-B1 interaction appears to mediate different and sometimes opposite effects depending on the cellular context. Plexin-B1 activation inhibits integrin-mediated cell attachment and cell migration through the activation of the R-RasGAP activity inherent to plexin-B1 or through the inhibition of RhoA. However, activation of plexin-B1 by Sema4D stimulates the migration of endothelial cells by mediating the activation of RhoA.