While melatonin was once thought of simply as a sleep-inducing hormone, recent research has resulted in development of a deeper understanding of the complex physiological activity of melatonin in the human body. Along with this understanding has come widespread, increasing use of melatonin supplementation, extending beyond its traditional use as a sleep aid into novel fields of application. This increased use often involves off-label and self-prescription, escalating the importance of safety data. In order to examine the current knowledge relating to safety of the exogenous neurohormone, we conducted a comprehensive, critical systematic review of clinical evidence. We examined controlled studies of oral melatonin supplementation in humans when they presented any statistical analysis of adverse events. Of the fifty articles identified, twenty-six found no statistically significant adverse events, while twenty-four articles reported on at least one statistically significant adverse event. Adverse events were generally minor, short-lived and easily managed, with the most commonly reported adverse events relating to fatigue, mood, or psychomotor and neurocognitive performance. A few studies noted adverse events relating to endocrine (e.g. reproductive parameters, glucose metabolism) and cardiovascular (e.g. blood pressure, heart rate) function, which appear to be influenced by dosage, dose timing and potential interactions with antihypertensive drugs. Oral melatonin supplementation in humans has a generally favourable safety profile with some exceptions. Most adverse effects can likely be easily avoided or managed by dosing in accordance with natural circadian rhythms. Further research is required to explore the potential for melatonin to interact with endogenous hormones and pharmaceuticals.