As the major components of the postsynaptic density of excitatory neuronal synapses, PDZ-domain-containing scaffold proteins regulate the clustering of surface glutamate receptors, organize synaptic signalling complexes, participate in the dynamic trafficking of receptors and ion channels, and coordinate cytoskeletal dynamics. These scaffold proteins often contain multiple PDZ domains, with or without other protein-binding modules, and they usually lack intrinsic enzymatic activities. Recent biochemical and structural studies have shown that tandemly arranged PDZ domains often serve as structural and functional supramodules that could regulate the organization and dynamics of synaptic protein complexes, thus contributing to the broad range of neuronal activity.