Colorectal cancer causes significant morbidity and mortality in the United States. The incidence of colorectal cancer can be reduced with increasing efforts directed at mass screening of average-risk adults 50 years and older. Currently, fecal occult blood test and flexible sigmoidoscopy have the highest levels of evidence to support their use for colorectal cancer screening. Colonoscopy does not have a proven colorectal cancer mortality benefit, but it does have the greatest single-test accuracy, and it is the final test in the pathway to evaluate and treat patients with other abnormal screening tests. Double-contrast barium enema has sparse data of effectiveness. Computed tomographic colonography, fecal DNA testing, and Pillcam Colon are promising tests that need further study before they can be recommended for widespread screening. Routine screening should continue until 75 years of age. There is good evidence that fiber and antioxidants are not effective for primary prevention of colorectal cancer; they should not be recommended for chemoprevention. There is good evidence that aspirin, nonsteroidal antiinflammatory drugs, and cyclooxygenase-2 inhibitors are effective for decreasing the risk of colorectal cancer and adenomatous polyps, but increased risks, such as gastrointestinal bleeding, limit their usefulness. There is fair evidence that obesity is associated with colorectal cancer. Additional studies are needed on decreased fat intake and red meat consumption, and the use of calcium, vitamin D, and statins before these can be recommended for primary prevention of colorectal cancer.