A variety of noninvasive molecular approaches to colorectal cancer screening are emerging with potential to improve screening effectiveness and user-friendliness. These approaches are based on the sensitive assay of molecular markers in stool, blood, and urine samples. New methods, especially next generation stool-based tests, have been shown to detect both colorectal cancers and precancerous lesions with high accuracy. Validation of these technologies in average-risk populations are needed to establish their role for general colorectal cancer screening. This review addresses the biological rationale, technical advances, recent clinical performance data, and remaining issues with molecular screening for colorectal cancer.