Since its discovery almost 60 years ago by Lerner and colleagues, melatonin (N-acetyl-5-metoxytryptamine), a hormone mainly produced in the pineal gland, has been the subject of numerous investigations aimed at establishing its physiological functions. The subsequent seminal observation that melatonin levels decrease during normal aging, combined with the facts that AD patients show melatonin deficits when compared to age-matched controls and that the extent of melatonin loss in the cerebrospinal fluid parallels the progression of the disease, was the starting point of a series of studies, conducted during the past 20 years, aimed at determining whether this non-peptide hormone could reasonably be considered as a possible promising anti-AD compound and at establishing through which mechanisms it can control the time course of the disease. In this context, particular attention has been paid to the amyloid peptide (Aβ), which, according to the now well accepted “amyloid cascade” hypothesis, is a key element of the pathology. Indeed, works performed in vitro and in vivo, thanks to the development of reliable mouse models of the pathology, consistently proved melatonin as an efficient anti-amyloid remedy when considering all the steps of Aβ biology (production, conformational changes, oligomerization, fibrillation and ultimately senile plaque formation). This review proposes to draw up a detailed inventory of our current knowledge on the subject with a particular focus on the recent advances in the field. Given the fact that melatonin conveys very few secondary effects, it is nowadays possible to seriously envision melatonin as an effective preventive anti-AD molecule.