Semaphorin-4D/CD100 (Sema4D) is a disulfide-linked homodimeric type 1 transmembrane glycoprotein belonging to the class IV family of membrane bound semaphorins. The extracellular domain of Sema4D contains a cysteine-rich semaphorin-like domain, an Ig-like domain, and a PSI domain . Research studies have suggested that the cytoplasmic domain has a signaling function as it is phosphorylated on serine residues . Initial studies involving Sema4D revealed that it was implicated in axon guidance within the central nervous system through binding its high affinity receptor, plexin-B1 . Sema4D function has also been extensively characterized in the immune system and is the first semaphorin found to be expressed on the surface of many types of immune cells . In the immune system, CD72 serves as a low-affinity receptor for Sema4D and research studies have shown that Sema4D not only regulates T-cell activation but is also involved in the regulation of B-cell survival and differentiation . Many of the physiologic effects of Sema4D in the immune system are regulated by a soluble extracellular domain-containing fragment generated through proteolytic cleavage .Sema4D has also been implicated in oncogenesis as research studies have demonstrated overexpression in multiple types of solid tumors . The role of Sema4D in oncogenesis, in part, has been linked to its ability to promote tumor angiogenesis , cell invasion , and immunosuppression through enhancement of myeloid derived suppressor cell function .