Wheat, as a staple food, has been largely consumed worldwide. In addition to nutritional values, whole grain including fiber-enriched wheat bran has been reported to provide many nutraceuticals such as wheat lignans. This chapter reviews recent epidemiological and animal data on wheat lignans and their role in colorectal cancer prevention. It covers aspects of the lignan structure, biosynthesis, analysis, metabolism and potential health benefits with emphasis on anti-proliferative, anti-oxidant, anti-inflammation, anti-estrogenic and cell cycle arrest mechanisms. Human epidemiological studies suggest dietary intake of lignans is associated with reducing risk of many chronic diseases such as cardiovascular disease, chronic bowel inflammation, and certain types of cancer including colorectal cancer. The bioactivity of wheat lignans has been shown to be influenced by their chemical forms and microbial flora-induced metabolites. Compelling animal study data suggest that dietary lignans or wheat lignans contribute to colorectal cancer prevention; however, further clinical intervention studies appear warranted.