Compared with our understanding of the electrophysiological correlates of sleep and wakefulness, the search for correlates at the molecular level is still in its infancy. However, the evidence obtained so far supports the hypothesis that reliable molecular correlates do exist. As will be summarized in this review, levels of receptor binding, second messengers and protein phosphorylation differ between sleep and wakefulness. Moreover, compelling data obtained in different animal species suggest that the transition between sleep and wakefulness is accompanied by significant changes in gene expression. Many immediate early genes, transcription factors, plasticity-related genes and mitochondrial genes are expressed at higher levels in wakefulness than in sleep, while a few still unknown genes are up-regulated during sleep. The ongoing systematic screening of gene expression across behavioural states should prove crucial in elucidating the regulatory mechanisms of sleep homeostasis and the functions of sleep.