Synapses join individual nerve cells into a functional network. Specific cell-cell signaling events regulate synapse formation during development and thereby generate a highly reproducible connectivity pattern. The accuracy of this process is fundamental for normal brain function, and aberrant connectivity leads to nervous system disorders. However, despite the overall precision with which neuronal circuits are formed, individual synapses and synaptic networks are also plastic and can readily adapt to external stimuli or perturbations. In recent studies, several trans-synaptic signaling systems have been identified that can mediate various aspects of synaptic differentiation in the central nervous system. It appears that these individual pathways functionally cooperate, thereby generating robustness and flexibility, which ensure normal nervous system function.