Abstract: Appropriate nervous system function depends on a precise but plastic neural architecture. Neuronal morphology determines how neurons interact with each other and with other cells. Every kind of neuron has its own morphological characteristics, which are determined by both intrinsic and extrinsic factors. In addition to intrinsic genetic programmes and patterns of neural activity, a variety of extrinsic factors regulate the growth and branching of neural processes and synaptogenesis. Work over the past decade has revealed that several members of the tumor necrosis factor superfamily (TNFSF) are potent positive and negative physiological regulators of neural process growth and branching in the developing nervous system without affecting neuronal survival. Extensively characterized in the immune system, where they play key roles in orchestrating and regulating immune responses, TNFSF members bind one or more members of the TNF receptor superfamily (TNFRSF), initiating canonical forward signaling. In addition, several TNFRSF members can act as ligands for the membrane-integrated TNFSF, triggering reverse signaling that has distinctive cellular responses to forward signaling (Eissner et al., 2004). In the developing nervous system, TNFSF/TNFRSF bidirectional signaling plays a major role in modulating neuronal architecture and has been studied most extensively for CD40 ligand (CD40L, TNFSF5) and CD40 (TNFRSF5).