The identification of the molecular correlates of sleep and wakefulness is essential to understand the restorative processes occurring during sleep, the cellular mechanisms underlying sleep regulation, and the functional consequences of sleep loss. To determine what molecular changes occur in the brain during the sleep-waking cycle and after sleep deprivation, our laboratory is performing a systematic screening of brain gene expression in rats that have been either sleeping or spontaneously awake for a few hours and in rats that have been sleep deprived for different periods of time ranging from a few hours to several days. So far, ~10,000 transcripts expressed in the cerebral cortex have been screened. The expression of the vast majority of these genes does not change either across behavioral states or after sleep deprivation, even when forced wakefulness is prolonged for several days. A few hours of wakefulness, either spontaneous or forced by sleep deprivation, increase the expression of the same small groups of genes: 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, and enzymes. Sleep, on the other hand, induces the expression of a few unknown transcripts whose characterization is in progress. Thus, although the characterization of the molecular correlates of behavioral states is not yet complete, 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. The pattern of changes in gene expression after long periods of sleep deprivation is unique and does not resemble that of short-term sleep deprivation or spontaneous wakefulness. A notable exception is represented, however, by the enzyme arylsulfotransferase, whose induction appears to be proportional to the duration of previous wakefulness. Arylsulfotransferase in rodents plays a major role in the catabolism of catecholamines, suggesting that an important role for sleep may be that of interrupting the continuous activity, during wakefulness, of brain catecholaminergic systems.