Screening of large populations for colon malignancy has been advocated in several countries to detect cancers at earlier, curable stages and/or prevent cancer by detecting and removing premalignant polyps. Ideal screening would identify subjects with the highest risk of cancer and target sensitive screening tests at this population. Recent data suggesting that environmental factors and genetic alterations contribute to increased cell proliferation in colonic mucosa provide several avenues for identification of high-risk subjects. This review examines the current literature regarding colon cancer risk factors, focusing on new ways to identify individuals who may benefit from targeted screening.