This article belongs to the Special Issue Advances in the Research of Melatonin. ; Melatonin modulates a wide range of physiological functions with pleiotropic effects on the immune system. Despite the large number of reports implicating melatonin as an immunomodulatory compound, it still remains unclear how melatonin regulates immunity. While some authors argue that melatonin is an immunostimulant, many studies have also described anti-inflammatory properties. The data reviewed in this paper support the idea of melatonin as an immune buffer, acting as a stimulant under basal or immunosuppressive conditions or as an anti-inflammatory compound in the presence of exacerbated immune responses, such as acute inflammation. The clinical relevance of the multiple functions of melatonin under different immune conditions, such as infection, autoimmunity, vaccination and immunosenescence, is also reviewed. © 2013 by the authors; licensee MDPI, Basel, Switzerland. ; The authors are grateful for financial support from the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (PI07/90175 and RD06/0013/0001), the PAIDI Program from the Andalusian Government (CTS160) and the Regional Government Ministry of Health (PI-0209-2010). ; Peer Reviewed