Melatonin is a hormone produced mainly in the pineal gland. Plasma levels exhibit a circadian variation with the highest concentration occurring at night. The human biologic effects of melatonin depend upon the time of day it is made available. One of these effects is the setting and resetting of circadian clocks (chronobiotic effect). Additionally, it may be a potent antioxidant and immunomodulator and has been shown to have antitumor, anticytokine, anti-insomnia, and anticachexia effects. Melatonin has also been shown to improve survival and performance status in patients with advanced cancer. Objective tumor response occurs with melatonin alone or when combined with interleukin-2 (IL-2). Further, melatonin reduces radiation- and chemotherapeutic-induced toxicity. Symptomatic and circadian disruption is linked to increased cancer risk. The chronobiotic capacity of melatonin to reset circadian clocks may provide a verifiable strategy to reduce cancer risk and enhance quality of life by diminishing cancer-induced circadian disruption.