Semaphorins--a family of secreted, membrane-bound, and transmembrane proteins--play an important role in the development of various organs, as well as in axonal pathfinding, angiogenesis, tumorigenesis, and the immunological response. Neuropilins 1 and 2 (NRP1 and 2) are receptors for the class 3 secreted semaphorins (SEMA3s) but not for the other classes of semaphorins. NRPs are also coreceptors for vascular endothelial growth factor 165 (VEGF165), suggesting that SEMA3s could inhibit the VEGF165-VEGF receptor (VEGFR) pathway during angiogenesis. Until recently, it was believed that binding of SEMA3s to neuropilins was necessary to initiate signaling from plexins, the active players in semaphorin signal transduction. However, Gu and colleagues have recently described an exception: Their research suggests that SEMA3E signal transduction may be neuropilin independent. This Perspective focuses on this recent finding in the context of semaphorin signaling outside the nervous system.