In vertebrate embryos, development of an architecturally optimized blood vessel network allows the efficient transport of oxygen and nutrients to all other tissues. The final shape of the vascular system results from vasculogenesis and angiogenesis, during which motile endothelial cells (ECs) modify their integrin-mediated interactions with the extracellular matrix (ECM) in response to pro- and anti-angiogenic factors. There is mounting evidence that different members of the semaphorin (SEMA) family of neural guidance cues participate in developmental and postnatal vessel formation and patterning as well. It turns out that paracrine secretion of class 3 SEMA (SEMA3) by nonendothelial tissues cooperates with vascular endothelial growth factor in regulating EC precursor migration and assembly during vasculogenesis and funnels navigating blood vessel through tissue boundaries during sprouting angiogenesis. Autocrine loops of endothelial SEMA3 instead appears to regulate vascular remodeling, which occurs through blood vessel intussusception and fusion. SEMA3 activity both on the vascular and nervous systems relies upon their ability to hamper the affinity of integrin receptors towards ECM ligands. Indeed, signaling from SEMA-activated plexin receptors negatively regulates cell-ECM adhesive interactions by inhibiting two key integrin activators, such as the small GTPase R-Ras and the focal adhesion protein talin.