OBJECTIVES:  Current options for colorectal cancer (CRC) screening include imaging procedures such as colonoscopy and flexible sigmoidoscopy, guaiac fecal occult blood tests (gFOBT), and fecal immunochemical tests (FIT).  Compliance with screening for CRC guidelines remains low among average-risk adults, at least partly because of low patient acceptance of available tests due to their invasiveness, inconvenience, and perceived safety risks. Serum tests are noninvasive, convenient, and safe, and may improve compliance. We systematically reviewed the literature to assess the current status of serum tests and other screening tests for CRC.  METHODS: We analyzed studies of CRC screening tests identified in a search of English-language MEDLINE-indexed articles published in the 3 years prior to March 2009 and non-MEDLINE-indexed sources such as organization websites, meeting abstracts, and government publications.  RESULTS: We identified 123 primary studies from MEDLINE and 45 from non-MEDLINE sources for a total of 168 pertaining to tests or biomarkers for early diagnosis of CRC. Serum biomarkers being evaluated include tumor associated antigens, cytokines, anti-apoptotic and pro-growth factors, and hypermethylated DNA. Biomarkers under development have significantly higher sensitivity for CRC than for adenomatous polyps, making them more effective for cancer detection than prevention. CRC sensitivity and specificity of certain serum biomarkers and serum biomarker panels under development are better than those of the existing test gFOBT and equivalent or better than those of FIT. However, most biomarkers in development are common to other cancers and diseases, reducing their specificity for CRC. CONCLUSIONS:  Several serum biomarkers show promise in detecting CRC, but require testing in large, average-risk populations. Unless biomarkers are identified that are more specific for adenomas and/or CRC than currently known, and because of the heterogeneity of CRC, the approach most likely to be successful would involve the combination of multiple serum biomarkers to create a distinctive CRC biomarker profile.