Chemopreventive strategies hold substantial promise for reducing the incidence of colorectal cancer, the second leading cause of cancer-related mortality in the United States. This review focuses on recent advances in the identification of molecular targets and novel strategies for chemopreventive intervention. Many clinical trials are now in progress to assess the ability of synthetic agents or nutritional supplements to alter either the number of colorectal adenomas or biomarkers associated with colorectal tumorigenesis. Populations under study include genetically defined high-risk people and those with increased risk based on a personal history of colorectal neoplasia. A recent study showing that celecoxib, a cyclooxygenase-2 inhibitor, can alter the natural history of polyp formation in patients with familial adenomatous polyposis has provided a benchmark for the clinical development of other chemopreventive agents and heightened awareness that colorectal cancer is a preventable disease.