Melatonin, the hormone of the pineal gland, orchestrates numerous physiological functions. High quantities of melatonin are also synthesized in various extrapineal sites. Melatonin's actions are partially mediated by the circadian multi-oscillator system, via effects on central and peripheral clocks. During aging, melatonin secretion declines and a progressive deterioration of the circadian system is observed. Decreases in melatonin levels also occur in various disorders and diseases, many of which are age-associated, particularly, dementias. Aging- and disease-related melatonergic dysfunction has given rise to the assumption that several senescence-associated pathologies may be corrected by melatonin substitution therapy. In fact, melatonin displays numerous properties of interest to gerontology. It is multiply involved in metabolic sensing, safeguarding mitochondrial function and integrity, reduction of free radical formation, detoxification of free radicals already formed, prevention of apoptosis, anti-excitatory mechanisms in the central nervous system, and anti-inflammatory actions, particularly by counteracting microglia activation. Up-regulation of the aging suppressor sirtuin-1, as observed in senescent mammals, comprises effects in metabolic control, mitochondrial proliferation, perhaps effects on telomere length, and improvements of circadian oscillator functions, because sirtuin-1 is an accessory clock component that enhances rhythm amplitudes. Collectively, available data indicate that melatonin may reduce inflammaging. In mammals, melatonin does not seem to strongly decelerate the basal aging processes. Thus, the lifespan of normally aging animals is only marginally extended. However, it is effective in reducing pathological symptoms of aging and in extending the lifespan of senescence-accelerated animals. Therefore, it appears to be a promising agent for promoting healthy aging.