Colorectal cancer (CRC) is still one of the leading causes of cancer-related death in Western countries, despite major improvements in its treatment. The dramatically high social and economic impact of CRC on human health makes the identification of a reliable screening tool of paramount importance. Current screening methods, such as the fecal occult blood test and colonoscopy do not adequately meet the ideal requisites of a screening test because, even if they are effective, they are limited first by too low specificity and sensitivity, or second by high invasiveness, costs and risk. Nowadays extended efforts are made by researchers to look for more reliable and effective screening tests based on a systems biology approach, using biological samples easily available, such as urine, breath, serum and feces. The effectiveness and reliability of several new attempts to screen these patients by non-invasive analysis of their biological samples using genomic (genetic and epigenetic alteration), transcriptomic (miRNA), proteomic (cancer-related antigens, new antibodies against tumor-associated antigens, mutated proteins) and metabolomic (volatile organic metabolites) methods are discussed in this review. Among the most interesting new screening tools, fecal fluorescent long-DNA, fecal miRNA and metabolomic evaluation in breath and/ or serum seem to be most promising. Coloradoctal cancer (CRC) is still one of the leading causes of cancer-related death in Western countries, despite major improvements in its treatment. The dramatically high social and economic impact of CRC on human health makes the identification of a reliable screening tool of paramount Current. Methods of screening, such as the fecal occult blood test and colonoscopy do not adequately meet the ideal requisites of a screening test because, even if they are effective, they are limited first by too low specificity and sensitivity, or second by high invasiveness , costs and risk. Nowadays extended efforts are made by researchers to look for more reliable and effective screening tests based on a systems biology approach, using biological samples easily available, such as urine, breath, serum and feces. The effectiveness and reliability of several new attempts to screen these patients by non-invasive analysis of their biological samples using genomic (genetic and epigenetic alterati on), transcriptomic (miRNA), proteomic (cancer-related antigens, new antibodies against tumor-associated antigens, mutated proteins) and metabolomic (volatile organic metabolites) methods are discussed in this review. Among the most interesting new screening tools, fecal fluorescent long-DNA, fecal miRNA and metabolomic evaluation in breath and / or serum seem to be most promising.