Colorectal cancer (CRC) screening in asymptomatic, average-risk populations can reduce mortality and incidence of CRC. The United States Preventive Services Task Force, the American Cancer Society, and the Multi-Society Task Force all recommend initiation of screening at the age of 50 yr for men and women of all races, with an identical menu of screening options. However, there are important differences in risk based on gender, race, and ethnicity. These differences could influence the timing of initiation of screening, and the most optimal form of screening test. This commentary discusses the basis for these differences, and proposes that we should consider customization of screening based on gender, race, and ethnicity.