The establishment of neuronal circuits requires neurons to develop and maintain appropriate connections with cellular partners in and out the central nervous system. These phenomena include elaboration of dendritic arborization and formation of synaptic contacts, initially made in excess. Subsequently, refinement occurs, and pruning takes places both at axonal and synaptic level, defining a homeostatic balance maintained throughout the lifespan. All these events require genetic regulations which happens cell-autonomously and are strongly influenced by environmental factors. This review aims to discuss the involvement of guidance cues from the Semaphorin family.