Multiprotein signalling complexes in the postsynaptic terminal of central nervous system synapses are essential for the induction of neuronal plasticity and cognitive processes in animals. The prototype complex is the N-methyl-D-aspartate receptor (NRC/MASC) complex, comprised of 185 proteins and embedded in the postsynaptic density (PSD), which is a set of complexes totalling ~1100 proteins. It is striking that 72% (5/7) of NRC/MASC genes and 46% (18/39) of the X chromosomal PSD genes are already known to be involved in human cognitive disorders. Furthermore, of the 67 known proteins mutated in X-linked metal retardation, 18 (27%) encode postsynaptic proteins. Over 50 of the NRC/MASC genes are involved in human diseases. Evolutionary studies suggest that mammalian MASC arose from a simpler ancestral form in metazoans and unicellular eukaryotes. The organisation of MASC proteins in these species may represent a ‘proto-synapse’. Developmental studies of MASC assembly using primary neurons suggests that a genetic transcriptional program may orchestrate synaptogenesis.