Stool DNA testing has evolved into what is now a highly accurate and well-validated test for the screen detection of colorectal neoplasia. An optimized and automated multi-target stool DNA test (MT-sDNA) has achieved the same high point-sensitivities as reported for colonoscopy and significantly higher sensitivity than by fecal immunochemical blood testing for detection of early-stage cancer and advanced precancer. Thus, MT-sDNA sets a new high criterion standard for the noninvasive screen detection of colorectal neoplasia. With clinical application, MT-sDNA has potential to meaningfully address current gaps in our approach to CRC screening through benefits of its high accuracy on screening effectiveness, user-friendly features on patient compliance, and easy mail-out distribution on test access. The US Food and Drug Administration and Center for Medicaid and Medicare Services have recently completed their parallel reviews of MT-sDNA, which has just become available for clinical use. This review summarizes the recent clinical validation data on MT-sDNA, addresses central clinical questions at this front end of implementation, and touches on innovative future applications of stool DNA testing.