We have recently demonstrated that c-fos expression is strongly induced by both spontaneous and forced wakefulness in many brain regions. c-Fos expression was considerably increased in regions involved in the regulation of arousal states, such as the locus coeruleus (noradrenergic neurons) and the medial preoptic area (non-GABAergic neurons). With c-fos antisense injection in the medial preoptic area, we demonstrated that c-fos expression in this region is causally involved in sleep regulation. c-Fos expression in other areas, such as the cerebral cortex and the hippocampus, may be related to the functional consequences of prolonged wakefulness and to the need of sleep. Further work should explore the mechanisms leading to changes in the expression of c-fos, and possibly of its target genes, during the sleep-wake cycle.