Comprehensive analysis of neuromuscular junction formation and recent data on synaptogenesis and long-term potentiation in the central nervous system revealed a number of extracellular matrix (ECM) molecules regulating different aspects of synaptic differentiation and function. The emerging mechanisms comprise interactions of ECM components with their cell surface receptors coupled to tyrosine kinase activities (agrin, integrin ligands, and reelin) and interactions with ion channels and transmitter receptors (Narp, tenascin-R and tenascin-C). These interactions may shape synaptic transmission and plasticity of excitatory synapses either via regulation of Ca2+ entry and postsynaptic expression of transmitter receptors or via control of GABAergic inhibition. The ECM molecules, derived from both neurons and glial cells and secreted into the extracellular space in an activity-dependent manner, may also shape synaptic plasticity through setting diffusion constraints for neurotransmitters, trophic factors and ions.