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Genetic manipulation of the 5-HT system leads to alterations of 5-HT neurotransmission and provides new opportunities to investigate the role of 5-HT in sleep regulations. Indeed, it represents an alternative to the use of pharmacological tools and, to some extent, of localized lesions of the 5-HT system, which have been, from the 1960s until recently, the main approaches to investigate this question. Homologous recombination knocking-out genes encoding various proteins involved in 5-HT neurotransmission in the mouse has recently allowed further assesment of the role of the serotonin transporter (5-HTT), the monoamine oxidase A (MAO-A), and the 5-HT1A, 5-HT1B and 5-HT2A receptors in the regulation of sleep. In 5-HT1A -/- and 5-HT1B -/- knock-out mice, Rapid Eye Movement sleep (REMs) was enhanced. Pharmacological blockade of these receptors had the same effects in wild-types. Thus, both receptor types exert a tonic inhibitory influence on REMs. In addition, 5-HT1A -/- and 5-HT1B -/- mutants were hypersensitive to 5-HT1B and 5-HT1A receptor agonists, respectively, which suggests that adaptive changes at 5-HT neurotransmission develop in knock-out animals. In the same manner, 5-HTT-/- knock-out mice exhibited increased REMs. This may be accounted for by a decrease in 5-HT1A and 5-HT1B receptor-mediated sleep regulations. In contrast, decreased REMs was observed in MAOA -/- knock-outs, a phenomenon that mimics the effect of pharmacological MAO inhibition. Finally, 5-HT2A -/- and 5-HT2C -/- mice exhibited more wakefulness and less slow wave sleep (SWS) than wild-types. These effects could not be reproduced by 5-HT2A or 5-HT2c receptor blockade in wild-types. To conclude, constitutive knock-outs undergo adaptive processes involving other proteins than those encoded by the invalidated gene, which renders interpretation of the corresponding sleep phenotype difficult. Inducible knock-outs will probably help to overcome this difficulty. Finally, combination of genetic manipulations with relevant pharmacological ones should allow further progress in the understanding of sleep mechanisms.