Colorectal cancer (CRC) is the third most common cancer in both men and women and is the third leading cause of cancer deaths in the United States. Incidence and mortality rates for CRC have declined over the past two decades, corresponding with an increase in self-reported screening rates. However, screening rates remain suboptimal. While different U.S. guideline-issuing organizations agree on the majority of recommended CRC screening options, there are differences between some recommended options, such as fecal DNA testing. In 2008, the United States Preventive Services Task Force (USPSTF) found that evidence was insufficient to recommend fecal DNA testing for CRC screening. However, the American Cancer Society (ACS), the U.S. Multi-Society Task Force (MSTF) on Colorectal Cancer, and the American College of Radiology (ACR) collectively recommended fecal DNA testing as an alternative screening method. The ACS-MSTF-ACR's recommendation was based on a lower threshold of evidence than that of the USPSTF. Fecal DNA tests are designed to detect molecular abnormalities in cells from cancer or precancerous lesions that are shed into the stool. Fecal DNA testing to screen for CRC has evolved significantly over time, both in improvements in understanding relevant molecular abnormalities associated with CRC and technological advances to allow for improved detection of molecular abnormalities in DNA in the stool. Molecular abnormalities that have served as the basis for CRC screening tests have focused on three major genetic mechanisms: chromosomal instability due to abnormalities in mutational hotspots like APC, KRAS, and TP53; microsatellite instability due to loss of function of mismatch repair genes that can result in accumulation of errors within the DNA sequence; and DNA methylation, an epigenetic alteration, in which promoter sites of genes are hypermethylated leading to suppression of gene transcription. This report includes six key questions to systematically review the evidence on fecal DNA testing to screen for CRC in average-risk adults. Key Question 1. Clinical utility: What is the effectiveness of fecal DNA testing (alone or in combination with other screening tests) to screen for CRC in reducing morbidity (CRC incidence) or mortality (all-cause or CRC-specific)? Key Question 2. Clinical validity: 2.1. What are the absolute test-performance characteristics (e.g., sensitivity, specificity) of fecal DNA testing for CRC screening, as compared to colonoscopy? a. To detect CRC? b. To detect precancerous lesion(s)? 2.2. What is the relative test performance of fecal DNA testing as compared to other established screening modalities in current practice? D. To detect CRC? E. To detect precancerous lesion(s)? Key Question 3. Interval of Screening: What is the test performance of fecal DNA testing across different screening interval(s)? Key Question 4. Analytic Validity: 4.1. What is the analytic validity (analytic sensitivity, specificity, and reproducibility) of currently available fecal DNA assays? 4.2. What are the important analytic and pre-analytic factors that can affect fecal DNA assay validity? Key Question 5. Acceptability of Testing: What is the acceptability and adherence of fecal DNA screening in comparison to other stool-based screening tests, or in comparison to more invasive modalities of screening? Key Question 6. Harms. What are the potential harms of fecal DNA testing?