Activation of glutamate receptors has been linked to a diversity of lasting physiologic and pathologic changes in the mammalian nervous system. The cellular and molecular mechanisms underlying permanent modifications of nervous system structure and function following brief episodes of neuronal activity are unknown. Immediate early genes (IEGs) have been implicated in the conversion of short-term stimuli to long-term changes in cellular phenotype by regulation of gene expression. Many of the long-term consequences of glutamate receptor activation correlate with increases in specific IEGs; the intracellular signalling pathways coupling activation of receptors at the cell surface with induction of IEGs in the nucleus are incompletely understood. Analysis of mechanisms of how extracellular factors control gene expression implicate activation of second messenger systems and protein kinases. Activation of glutamate receptors results in an initial increase in intracellular calcium; the route of calcium influx may differ depending on the specific receptor subtype activated. Intracellular calcium is often the first messenger in response to an extracellular stimulus and can be the trigger for activating numerous other signalling pathways. Results obtained over the past several years support a hypothesis where selective activation of distinct intracellular signalling pathways and IEG responses, following activation of different glutamate receptor subtypes, involve spatial restriction of key enzymes to sites of local calcium increases. The specificity in long-term neuronal responses following brief synaptic activation may depend on the specific intracellular signalling mechanisms triggered and the unique array of IEGs transcribed.