Several decades of observational data have accumulated to implicate a potential role for melatonin in cancer prevention. Experimental studies suggest that the antineoplastic action of melatonin arises through many different mechanisms, including melatonin's antioxidant, antimitotic, and antiangiogenic activity, as well as its ability to modulate the immune system and alter fat metabolism. Melatonin interacts with membrane and nuclear receptors, and may be linked to the regulation of tumor growth. Of particular relevance to breast cancer risk, melatonin may also block the estrogen receptor ERalpha and impact the enzyme aromatase, which produces estradiol. A growing number of epidemiologic studies have evaluated the relationship between night shift work as well as how varying duration of sleep affects peak melatonin secretion at night. While the studies demonstrate lower nightly melatonin levels in night workers, the evidence for an association between sleep duration and melatonin production is less clear. Similarly, both case-control and prospective cohort studies have consistently linked night shift work with breast cancer risk and, more recently, endometrial cancer - another tumor highly sensitive to estrogens. While, to date, the evidence for an association between sleep duration and breast cancer risk is less convincing, overall, there is increasing support for a potentially important link between melatonin and breast cancer risk and perhaps the risk of other tumors. As evidence increases, modifiable factors that have been shown to affect melatonin production, such as night shift work, are likely to gain increasing recognition as potential public health hazards. Additional studies are needed to delineate further the potential of melatonin in cancer prevention.