Knowledge of the molecular correlates of sleep and wakefulness is essential if we are to understand the restorative processes occurring during sleep and the cellular mechanisms underlying sleep regulation. In order to determine what molecular changes occur during the sleep-waking cycle, we have recently performed a systematic screening of gene expression in the brain of sleeping, sleep deprived and spontaneously awake rats. Out of the approximately 10 000 genes screened so far, a small minority ( approximately 0.5%) was differentially expressed in the cerebral cortex across behavioral states. Most genes were upregulated in wakefulness and sleep deprivation relative to sleep, while only a few had higher expression in sleep relative to wakefulness and sleep deprivation. Almost all the genes upregulated in sleep, and several genes upregulated in wakefulness and sleep deprivation, did not match any known sequence. Known genes that were upregulated in wakefulness and sleep deprivation could be grouped into functional categories: immediate early genes/transcription factors, genes related to energy metabolism, growth factors/adhesion molecules, chaperones/heat shock proteins, vesicle- and synapse-related genes, neurotransmitter/hormone receptors, neurotransmitter transporters, enzymes, and others. Although the characterization of the molecular correlates of sleep, wakefulness and sleep deprivation is still in progress, it is already apparent that the transition from sleep to waking can affect basic cellular functions such as RNA and protein synthesis, neural plasticity, neurotransmission, and metabolism.