Secreted class 3 semaphorins (Sema3), which signal through plexin receptors and mostly use neuropilins (Nrps) as co-receptors, were initially identified for their ability to steer navigating axons in the developing embryo. They were later found to control angiogenesis in physiological and pathological settings as well (Serini et al, 2013). Indeed, the development of a novel and aberrant vasculature is central to the pathogenesis of several human diseases, including cancer and vascular retinopathies (Goel et al, 2011). A large body of evidence demonstrates that in cancer, a massive regression of angiogenesis may trigger hypoxia-driven genetic programs, which in turn can overcome drug inhibitory mechanisms and ultimately favour cancer cell invasion and dissemination. Thus, an emerging concept in molecular medicine is to devise therapeutic strategies that, rather than simply inhibiting angiogenesis, can foster the re-establishment of a structural and functional normal network, a phenomenon often referred to as “vessel normalization” (Goel et al, 2011) (Fig 1). Of note, and in this context, Sema3A (Maione et al, 2009) and Sema3F (Wong et al, 2012) have been reported to favour the normalization of cancer vasculature and impair metastatic dissemination.