After 2 screen-setting studies showing high sensitivity for colorectal cancer and advanced precancerous lesions, multitarget stool DNA testing was endorsed by the US Preventative Services Task Force as a first-line colorectal cancer screening test. Uptake has increased exponentially since approval by the US Food and Drug Administration and Centers for Medicare and Medicaid Services. Adherence to testing is approximately 70%. Patients with positive results have high diagnostic colonoscopy completion rates in single-center studies. The positive predictive value for colorectal neoplasia in postapproval studies is high. Next-generation test prototypes show promise to extend specificity gains while maintaining high sensitivity.