Assay of molecular markers in stool represents a promising noninvasive approach to screen colorectal cancer. Given that neoplasms exfoliate abundantly into the lumen and that DNA recovered from stool can be assayed with sensitive techniques, there is a strong biologic rationale to pursue this emerging technology. A challenge with DNA-based testing relates to the selection of markers. Because of the molecular heterogeneity of cancer, no single marker has yielded perfect sensitivity. Several combinations of markers in early stool assays have produced high detection rates of both colorectal cancer and advanced adenomas in selected patient groups, but observations from large representative populations are lacking at present. Potential expanded applications of stool DNA testing include detection of supracolonic aerodigestive cancers and of dysplasia in inflammatory bowel disease. Further marker discovery and technologic refinements should translate into improved test performance and fuel a continued evolution with this screening approach.