Semaphorins are a family of cell surface and secreted proteins that are conserved from insects to humans. Members of this family of proteins are approximately 750 amino acids in length (including signal sequences) and are defined by a conserved extracellular “semaphorin” domain of approximately 500 amino acids containing 14-16 cysteines, blocks of conserved sequences and no obvious repeats. Secreted and cell-bound semaphorins chemically attract and repel the growth of neural axons, guiding the development of intricate networks of neural tissue. SEMA5B (semaphorin-5B), also known as SEMAG, is a 1151 amino acid member of the semaphorin family. Localized to the membrane, SEMA5B is a single-pass type III protein that functions to convey positive axonal guidance cues and can induce calpain-mediated cleavage of calcineurin. Three isoforms exist due to alternative splicing events.