Melatonin (N-acetyl-5-methoxytryptamine) is mainly secreted by the pineal gland at the hypothalamic level, as well as in the gastrointestinal tract. Melatonin synthesis occurs mainly at night and is inhibited by the sunlight (Axelrod et al. 1965, Pandi-Perumal et al. 2008). Epidemiological studies have clearly demonstrated that high levels of melatonin decrease the risk of developing cancer (Alpert et al. 2009, Flynn-Evans et al. 2009, Kliukiene et al. 2001, Kloog et al. 2008, Lipton et al. 2009, Schernhammer and Hankinson 2009, Schernhammer et al. 2008, 2010). In particular, two epidemiological studies have demonstrated an inverse correlation between overnight urinary levels of melatonin and the incidence of breast cancer (Schernhammer and Hankinson 2009, Schernhammer et al. 2008). The rst, conducted within the ORDET cohort, tested the concentration of the melatonin metabolite 6-sulfatoxymelatonin (aMT6s) in 178 postmenopausal women with incident breast cancer and 710 matched controls (Schernhammer and Hankinson 2009). The second one is a case-control study conducted within the NHIS cohort on 357 postmenopausal women with incident breast cancer and 533 matched controls, in which the authors found that there was a negative correlation between aMT6s levels and the risk of invasive breast cancer, regardless of ER and Her2 status (Schernhammer and Hankinson 2009). Light at night (LAN), which causes reduced melatonin levels, is believed to increase the incidence of breast cancer: blindness has an inverse correlation with breast cancer because the total absence of LAN in totally blind people leads to inhibition of nocturnal decrease of melatonin production by light (Blask et al. 2011, Reiter et al. 2007); on the contrary, exposure to LAN in night-shift workers reduces melatonin production during night and therefore increases cancer risk (Blask et al. 2011) as well as exposure of animals to long light periods enhances the growth of chemically induced carcinomas in female rats (Cos et al. 2006). Along the same line, when mouse xenografts and rat hepatomas are perfused with blood collected at night from healthy premenopausal women, they show a marked suppression in proliferation as compared with tumors perfused with blood collected during daytime and therefore melatonin-depleted (Blask et al. 2005). The same type of results has been observed in men: LAN exposure increases the risk of developing cancer at several sites (Parent et al. 2012). These studies suggest that melatonin 18.1 Introduction. …………………………………………………………………………………………………………. 223 18.2 Melatonin Receptors. ………………………………………………………………………………………………224 18.3 Melatonin Receptors and Cancer. ……………………………………………………………………………..224 18.4 Conclusions and Perspectives. …………………………………………………………………………………. 227 References. …………………………………………………………………………………………………………………….228.