Plexins are a family of large integral membrane proteins that complex with neuropilins to form semaphorin co-receptors. The extracellular region of plexins contains a semaphorin domain, multiple glycine-rich motifs, and MET-related sequences. The cytoplasmic region contains a Sex/Plexin domain and putative tyrosine phosphorylation sites that mediate signal transduction after activation. Plexin D1 is a type I transmembrane protein that may be expressed as multiple isoforms in many cell types, including neurons and endothelial cells. Semaphorin 3E (Sema-3E) and semaphorin 4A can bind Plexin D1, and ligand binding leads to phosphorylation of Tyr-1642 and activation of Plexin D1. Sema-3E and its receptor are important for angiogenesis that occurs during blood vessel development and repair. In cancers, Sema-3E and Plexin D1 are expressed in tumor tissues and cancer cells, and the interaction of these molecules may promote cancer cell migration and metastic spreading. Thus, Plexin D1, and its ligand Sema-3E, may be important regulators of angiogenesis and metastasis.