Nutritional factors play an important role in the prevention and promotion of colorectal cancer. Vitamin E is a generic term that describes a group of lipid-soluble chain-breaking antioxidants that includes tocopherols and tocotrienols. Vitamin E occurs in nature as eight structurally related forms that include four tocopherols and four tocotrienols. Vitamin E is a potent membrane-soluble antioxidant. Antioxidants like vitamin E (tocopherols) may prevent colon cancer through several different cellular and molecular mechanisms. Vitamin E in the American diet is primarily available in plant-oil rich foods such as vegetable oils, seeds and nuts and these foods vary widely in their content of alpha-tocopherol and gamma-tocopherol. Vitamin E may help prevent colon cancer by decreasing the formation of mutagens arising from the oxidation of fecal lipids, by decreasing oxidative stress in the epithelial cells of the colon and by molecular mechanisms that influence cell death, cell cycle and transcriptional events. Most epidemiological, experimental and clinical studies have evaluated the alpha-isoform and not the gamma-isoform of vitamin E. Recent epidemiological, experimental and mechanistic evidence suggests that gamma-tocopherol may be a more potent cancer chemopreventive agent than alpha-tocopherol. The differences in chemical reactivity, metabolism and biological activity may contribute to these differences in the effects of gamma-tocopherol when compared with alpha-tocopherol. The rationale supporting the development of gamma-tocopherol as a colorectal cancer preventive agent is reviewed here.