Colorectal cancer (CRC) is the third most prevalent cancer, with approximately one million cases estimated world wide in 2006, resulting in more than 500,000 deaths. Approximately 40% of colorectal cancers are diagnosed with localized disease, which have approximately a 90% five-year survival rate. However, the prognosis worsens with advancing stage, and only 5% of patients diagnosed with distant metastases survive 5 years. Therefore, the need for early detection is clear. Currently, guaiac-based fecal-occult blood testing (gFOBT) in large population-based trials has been shown to reduce CRC-related mortality, but the sensitivity for detecting early disease is low. DNA-based fecal screening appears to have the potential to significantly increase sensitivity without decreasing specificity. This review will focus primarily on newer molecular-based biomarkers and their utility in screening large populations for CRC, predicting treatment efficacy and providing prognostic information related to survival and disease progression.