The authors have shown that, via activation of its MT1 receptor, melatonin modulates the transcriptional activity of various nuclear receptors and the proliferation of both ERα+ and ERα- human breast cancer cells. Employing dominant-negative (DN) and dominant-positive (DP) G proteins, it was demonstrated that Gα i2 proteins mediate the suppression of estrogen-induced ERα transcriptional activity by melatonin, whereas the Gαq proteins mediate the enhancement of retinoid-induced RARα transcriptional activity by melatonin. In primary human breast tumors, the authors’ studies demonstrate an inverse correlation between ERα and MT1 receptor expression, and confocal microscopic studies demonstrate that the MT1I receptor is localized to the caveoli and that its expression can be repressed by estrogen and melatonin. Melatonin, via activation of its MT1 receptor, suppresses the development and growth of breast cancer by regulation of growth factors, regulation of gene expression, regulation of clock genes, inhibition of tumor cell invasion and metastasis, and even regulation of mammary gland development. The authors have previously reported that the clock gene, Period 2 ( Per2), is not expressed in human breast cancer cells but that its reexpression in breast cancer cells results in increased expression of p53 and induction of apoptosis. The authors demonstrate that melatonin, via repression of RORα transcriptional activity, blocks the expression of the clock gene BMAL1 . Melatonin’s blockade of BMAL1 expression is associated with the decreased expression of SIRT1, a member of the Silencing Information Regulator family and a histone and protein deacetylase that inhibits the expression of DNA repair enzymes (p53, BRCA1 & 2, and Ku70) and the expression of apoptosis-associated genes. Finally, the authors developed an MMTV-MT1-flag mammary knock-in transgenic mouse that displays reduced ductal branching, ductal epithelium proliferation, and reduced terminal end bud formation during puberty and pregnancy. Lactating female MT1 transgenic mice show a dramatic reduction in the expression of β-casein and whey acidic milk proteins. Further analyses showed significantly reduced ERα expression in mammary glands of MT1 transgenic mice. These results demonstrate that the MT1 receptor is a major transducer of melatonin’s actions in the breast, suppressing mammary gland development and mediating the anticancer actions of melatonin through multiple pathways.