Detection of advanced colorectal neoplasia (advanced adenoma or cancer) in the course of screening programs has been proven to reduce both the incidence and mortality of the disease. In the average-risk population, the most extended colorectal cancer (CRC) screening strategies are based either on annual or biennial fecal occult blood tests, with colonoscopy reserved for patients testing positive, or on endoscopic procedures performed as the primary screening tool every 5 (sigmoidoscopy) or 10 (colonoscopy) years. In addition, other screening procedures, such as CT colonography and fecal DNA analysis, are under current investigation. However, several drawbacks associated with these techniques have led to low acceptability and compliance rates in population-based screenings. Therefore, there is a compelling need to identify noninvasive biomarkers to enhance screening acceptance and efficacy in detecting CRC at an earlier and curable stage. Although the analysis of blood biomarkers has not been included among the recommended strategies for CRC screening yet, recent advances in proteomics and genomics suggest that these technologies may represent alternative or complementary approaches to the currently accepted strategies in the near future. However, the accuracy of these techniques in terms of sensitivity, specificity, and predictive values for early detection of CRC must be confirmed in mass screening studies.