Secreted class 3 semaphorins (Sema3), which signal through holoreceptor complexes that are formed by different subunits, such as neuropilins (Nrps), proteoglycans, and plexins, were initially characterized as fundamental regulators of axon guidance during embryogenesis. Subsequently, Sema3A, Sema3C, Sema3D, and Sema3E were discovered to play crucial roles in cardiovascular development, mainly acting through Nrp1 and Plexin D1, which funnels the signal of multiple Sema3 in vascular endothelial cells. Mechanistically, Sema3 proteins control cardiovascular patterning through the enzymatic GTPase-activating-protein activity of the cytodomain of Plexin D1, which negatively regulates the function of Rap1, a small GTPase that is well-known for its ability to drive vascular morphogenesis and to elicit the conformational activation of integrin adhesion receptors.