The field of colon cancer screening has evolved dramatically in the last 15 years regarding evidence, guidelines, and practice. In 1990, no evidence from a randomized controlled clinical trial (RCT) existed to show that colorectal cancer (CRC) screening was effective in reducing CRC mortality. In 1990, although some guidelines endorsed screening, there was disagreement among recommending organizations about which tests to recommend or whether to recommend any screening tests at all. The US Preventive Services Task Force (USPSTF), arguably the most influential of the recommending organizations and the most rigorously evidence based, said that evidence was insufficient to recommend either for or against CRC screening.1 In this environment, CRC screening was not widely practiced, much less reimbursed by payers. If screening was performed at all, fecal occult blood testing (FOBT) was the most common test. Sigmoidoscopy was performed less frequently, and colonoscopy, rarely performed for screening, was used mainly for workup of a positive FOBT or sigmoidoscopy and for postpolypectomy surveillance. The primary questions facing academics, recommending organizations, and practicing clinicians in 1990 were (1) does CRC screening—of any kind—work to reduce CRC mortality, and (2) should it be implemented and reimbursed? In 2005, the situation is dramatically different. We now know that CRC screening works, and it is now being implemented and reimbursed. Colonoscopy has become popular as a primary screening test, and new tests, such as virtual colonoscopy, are being developed. The purpose of this article is to identify current challenges in light of the evolution of evidence, guidelines, and practice and to anticipate the next phase of development and implementation.