Despite recent declines in both incidence and mortality, colorectal cancer (CRC) remains the second most common cause of cancer death in the United States. Screening for CRC reduces mortality through the detection of malignancies at earlier, more treatable stages, as well as through the identification and removal of adenomatous polyps (asymptomatic benign precursor lesions that may lead to CRC). There are a number of tests currently available for screening, such as fecal occult blood testing (FOBT), flexible sigmoidoscopy, and colonoscopy. Screening with FOBT (Hemoccult II) has been shown to reduce CRC mortality by 15% to 33% in randomized controlled trials and screening with more sensitive FOBTs, flexible sigmoidoscopy, colonoscopy or combinations of these tests may reduce the burden of CRC even more. In the absence of adequate clinical trial data on several recommended screening strategies, microsimulation modeling can provide guidance on the risks, benefits, and testing resources required for different screening strategies to reduce the burden of CRC. In July 2002, the US Preventive Services Task Force (USPSTF) concluded that there was sufficient evidence to recommend strongly that all average-risk adults 50 years of age and older should be offered CRC screening. However, the logistics of screening such as the type of screening test, screening interval, and age to stop screening were not evaluated in terms of the balance of benefits and potential harms. The USPSTF has again addressed CRC screening recommendations with a systematic review of the evidence on screening tests. For this assessment, the Task Force requested a decision analysis to project expected outcomes of various CRC screening strategies. Two independent microsimulation modeling groups from the Cancer Intervention and Surveillance Modeling Network (CISNET), funded by the National Cancer Institute, used a comparative modeling approach to compare life-years gained relative to resource use of different CRC screening strategies.