Chemical synapses allow neurons to perform complex computations and regulate other systems of the body. At a chemical synapse, pre- and postsynaptic sites are separated by a small space (the synaptic cleft) and surrounded by astrocytes. The basement membrane (BM), a sheetlike, specialized extracellular matrix (ECM), is found ubiquitously in the PNS. It has become clear that the ECMs not only play a structural role but also serve as barriers and filters in the PNS and CNS. Moreover, proteoglycans and tenascin family proteins in the ECM regulate synapse formation and synaptic plasticity. Although CNS synapses lack the BMs, recent results indicate that the BM-associated collagens are also present in the CNS synaptic cleft and affect synaptogenesis in both the CNS and the PNS. The C1q domain-containing family proteins are important components of the CNS synaptic cleft in regulating synapse formation, maintenance, and the pruning process. The ECM is regarded as a crucial component of the tetrapartite synapse, consisting of pre- and postsynaptic neurons, astrocyte, and ECM.