Dream-enactment behavior that emerges during episodes of rapid eye movement (REM) sleep without muscle atonia is a parasomnia known as REM sleep behavior disorder (RBD). RBD constitutes a prodromal marker of α-synucleinopathies and serves as one of the best biomarkers available to predict diseases such as Parkinson disease, multiple system atrophy and dementia with Lewy bodies. Most patients showing RBD will convert to an α-synucleinopathy about 10 years after diagnosis. The diagnostic advantage of RBD relies on the prolonged prodromal time, its predictive power and the absence of disease-related treatments that could act as confounders. Therefore, patients with RBD are candidates for neuroprotection trials that delay or prevent conversion to a pathology with abnormal α-synuclein metabolism. The administration of melatonin in doses exhibiting a chronobiotic/hypnotic effect (less than 10 mg daily) is commonly used as a first line treatment (together with clonazepam) of RBD. At a higher dose, melatonin may also be an effective cytoprotector to halt α-synucleinopathy progression. However, allometric conversion doses derived from animal studies (in the 100 mg/day range) are rarely employed clinically regardless of the demonstrated absence of toxicity of melatonin in phase 1 pharmacological studies with doses up to 100 mg in normal volunteers. This review discusses the application of melatonin in RBD: (a) as a symptomatic treatment in RBD; (b) as a possible disease-modifying treatment in α-synucleinopathies. To what degree melatonin has therapeutic efficacy in the prevention of α-synucleinopathies awaits further investigation, in particular multicenter double-blind trials.