Increases in intraneuronal free calcium result in the rapid, transient, induction of the fos and jun proto-oncogenes. In PC12 cells, induction may be elicited either by membrane depolarization or by direct activation of voltage-dependent calcium channels with BAY K 8644 both of which provoke an influx of calcium. The calmodulin pathway appears to link the elevated intracellular calcium to gene induction. In the brain, c-fos and c-jun may be induced by elevated neuronal activity such as occurs during pentylenetetrazole (PTZ) seizures. The N-methyl-D-aspartate (NMDA) form of the glutamate receptor, which can directly gate calcium, plays a role in the induction of c-fos expression in PTZ seizures. In addition, NMDA can directly stimulate c-fos in the brain. Fos and Jun form a noncovalent nucleoprotein complex that binds to the consensus recognition sequence of the AP-1 transcription factor. Thus in a larger picture we envisage Fos and Jun as members of a concerted stimulus-transcription coupling pathway that links alterations in external stimuli to long term adaptive responses. In this context Fos, Jun and the other immediate-early genes should be viewed as third messengers which are regulated by second messengers such as intracellular calcium.