<p>Semaphorins were first cloned as recognised mediators of cellular guidance, and consist of a large family of phylogenetically conserved secreted and transmembrane signalling proteins. Among the best-characterised vertebrate Semaphorins are the five secreted Class 3 members that contain an approximately 500 amino acid N-terminal Semaphorin domain, a C2 type immunoglobulin domain, and a highly basic C-terminal tail [<cite idref="PUB00034855"/>]. Two receptor families have been implicated in mediating the actions of class 3 semaphorins: the Neuropilins and Plexins. The nine known vertebrate Plexins are divided into four subfamilies (A through D) based on structure [<cite idref="PUB00034856"/>]. Several Plexins have been shown to interact directly with some class 4, 7 and V Semaphorins, but class 3 Semaphorins, however, do not appear to bind Plexins directly. Rather, the functional receptors for these Semaphorins are complexes of Neuropilins and A-type Plexins, with the former serving as the ligand-binding moiety and the latter the signal-transducing component [<cite idref="PUB00034856"/>, <cite idref="PUB00034857"/>]. There are two Neuropilins (NP-1 and NP-2) that bind the five class 3 Semaphorins preferentially. In particular, Sema3A binds NP-1, whereas Sema3F utilises NP-2, while NP-1 and NP-2 heterodimers are thought to serve as functional receptors for Sema3C [<cite idref="PUB00034858"/>].</p> <p>Although Semaphorins were originally appreciated for their role in axonal guidance, PlexinB1 has been shown to also be involved in angiogenesis [<cite idref="PUB00035195"/>], immunity [<cite idref="PUB00035196"/>], and metastasis [<cite idref="PUB00035197"/>].</p>