Increasing evidence suggests that lycopene, a major carotenoid detected in human plasma, may be preventive against the formation and the development of different types of human cancers including prostate, breast, and lung cancer. Experimental studies demonstrated that lycopene inhibits the growth of various cancer cells of different organs and prevent chemically induced carcinogenesis in animal models. Although the excellent antioxidant property of lycopene is most likely the basis for its preventive role toward cancer, the direct anticancer activities of lycopene through multiple mechanisms are disclosed, including regulation of growth factor signaling, cell cycle arrest and/or apoptosis induction, and changes in antioxidant and phase II detoxifying enzymes. The anti-inflammatory activity of lycopene is also considered as an important determinant that suppresses the promotion and progression of carcinogenesis. Moreover, lycopene inhibits cell invasion, angiogenesis, and metastasis. Importantly, those activities have been shown to be exhibited at the physiologically attainable concentration in humans. Although the preclinical data strongly suggest an antitumor activity of lycopene, a number of epidemiological and intervention studies indicate that there is still no clear clinical evidence that supports its use for the prevention of those cancers. More well controlled clinical intervention trials are needed to further clarify the exact role of lycopene in the cancer prevention. Nonetheless, because of its multiple tumor-inhibitory activities, lycopene still remains to be an attractive and promising carotenoid that will potentially contribute to the prevention and treatment of human cancers. This chapter reviews data on the cancer preventive activities of lycopene, possible mechanisms involved, and the relationship between lycopene consumption and human cancer risk. © 2015 Elsevier Inc.