The exposure to light once stopped after sunset. However, the discovery of artificial light has prolonged light exposure late into the night. This shift has shown to have an impact on women working night shifts, as their melatonin production, which rely on absolute darkness, is inhibited. The reduction in serum melatonin and circadian disruption are associated with an increased risk for breast cancer. Moreover, the supplementation of melatonin has been shown to restore circadian rhythm and produce an anti-cancer response. However, the combined treatment of chemotherapy and melatonin do not always produce desirable results in all patients. It remains elusive why some patients respond while others do not to the combined treatment with melatonin. This highlights the importance of the true understanding of mechanisms regarding the restoration of circadian rhythm and melatonin anticancer properties. Our unpublished cDNA array data of FOXM1 and FOXO3 revealed that several genes of the circadian rhythm is regulated by FOXM1 and FOXO3. Moreover, bioinformatic analysis of chromatin immunoprecipitation with DNA sequencing (ChIP-seq) show that FOXM1 and FOXO3 binds to the promoters of these circadian components. Additionally, studies have provided links between the forkhead transcription factors and the circadian rhythm. Here, I found that the FOXM1-FOXO3 axis indeed regulates the core circadian genes: CLOCK, ARNTL(BMAL), CRY1, CRY2, PER1, and PER2. Furthermore, melatonin plays a role in this regulation by targeting the upstream pathways leading to FOXM1-FOXO3 axis, including the p38, AMPK, JNK, and AKT pathways. Lastly, the FOXM1-FOXO3 profile plays a critical role in the response of drug-resistant breast cancer to melatonin as well as melatonin combination treatment.