SH3 and multiple ankyrin repeat domains 1-3 (Shank1-3) of the Shank/ProSAP family are molecular scaffolds in the postsynaptic density (PSD). The PSD is an electron-dense structure underneath the postsynaptic plasma membrane of excitatory synapses that anchors and clusters glutamate receptors opposite to the presynaptic neurotransmitter release site. Shank proteins contain PDZ modular domains that coordinate the synaptic localization of ion channels, receptors, signaling enzymes, and cell adhesion molecules. The PDZ domain mediates protein-protein interactions via the recognition of a conserved sequence motif at the C-terminus of their target protein(s). Shank recruits betaPIX and PAK to spines to regulate postsynaptic structure and interacts with NMDA receptor and metabotropic glutamate receptor complexes. Transcript splice variation in the Shank family influences the spectrum of Shank-interacting proteins in the PSDs of adult and developing brain to ensure normal development.