The serotoninergic system is involved in the regulation of sleep and wakefulness, its activity being at maximum during the awake state and minimum during sleep. In particular, the production of rapid eye movement (REM) sleep depends on the decrease of serotoninergic tone in brain stem structures. Thus, serotoninergic compounds which increase this tone (such as antidepressants) induce inhibition of REM sleep. Depression is associated with a functional decrease of serotoninergic neurotransmission and with specific alterations of sleep, notably insomnia. Paradoxically, even though they complain of sleep loss, depressed patients exhibit significant mood improvement after one night of sleep deprivation. This antidepressant effect can be accounted for by the same serotoninergic mechanisms as those described for pharmacological treatments. Indeed, the therapeutic action of antidepressants such as selective serotonin reuptake inhibitors is thought to depend directly on the enhancement of central serotoninergic neurotransmission. Such enhancement is achieved through desensitization of serotoninergic autoreceptors, which results from chronic treatment with these compounds. Sleep deprivation also induces an activation of serotoninergic neurons due to prolonged wakefulness, and leads to similar serotoninergic adaptive processes. The common neurobiological mechanisms resulting from pharmacological antidepressant treatment and sleep deprivation suggest that sleep loss in some insomniac or in depressed patients might be an endogenous compensatory process which would be therapeutical rather than pathological. This proposal should open the way to new strategies in the treatment of depression.