Although the circadian time-keeping properties of the suprachiasmatic nuclei (SCN) require gene expression, little is known about the signal transduction pathways that initiate transcription. Here we report that a brief exposure to light during the subjective night, but not during the subjective day, activates the p44/42 mitogen-activated protein kinase (MAPK) signaling cascade in the SCN. In addition, MAPK stimulation activates CREB (cAMP response element binding protein), indicating that potential downstream transcription factors are stimulated by the MAPK pathway in the SCN. We also observed striking circadian variations in MAPK activity within the SCN, suggesting that the MAPK cascade is involved in clock rhythmicity.