The CNS is both source and target of melatonin. It is released from the pineal to the circulation and, in elevated concentrations, into the third ventricle. Levels by 3 orders of magnitude higher than in the circulation have been found in the CNS. The mammalian circadian pacemaker, suprachiasmatic nucleus (SCN), controls the pineal, but is also major subject to feedback information on darkness, transduced by two G-protein coupled melatonin receptors, MT1 and MT2, which cause suppression of neuronal firing and circadian phase resetting. Two MT1 and MT2 agonists, ramelteon and agomelatine, display sleep-promoting properties. Agomelatine additionally inhibits 5-HT2C receptors, the basis of an antidepressant effect. Melatonin, ramelteon and agomelatine have been tested in clinical trials. Only ramelteon has received approval by the FDA, as a sleeping pill. Bioactive melatonin analogs, N-acetylserotonin, 5-methoxytryptamine, N,Ndimethyl- 5-methoxytryptamine, and 5-methoxytryptophol are produced in the CNS. Interplays between these compounds, including the serotoninergic system, are likely. N-Acetylserotonin is abundant in hippocampus, cerebellum, midbrain, pons and medulla. Neuroprotective actions of melatonin include antiamyloidogenic, antiexcitatory/antiexcitotoxic, antioxidant effects and modulation of mitochondrial metabolism, with consequences for radical formation and aging. The remarkable pleiotropy of melatonin includes other binding sites, such as calmodulin, calreticulin and a nuclear calreticulin homolog, members of the ROR/RZR family, quinone reductase 2 and specific mitochondrial sites. N1-acetyl-N2-formyl-5- methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK) are major melatonin metabolites in the CNS and also display biological activities. For instance, AMK inhibits neuronal NO synthase already at 10-11 M, and modulates mitochondrial metabolism. By interacting with NO, AMK forms 3-acetamidomethyl-6-methoxycinnolinone (AMMC).