Colonoscopy is the dominant colorectal cancer screening strategy in the USA. There are no randomized controlled trials completed of screening colonoscopy, but multiple lines of evidence establish that colonoscopy reduces colorectal cancer incidence in both the proximal and distal colon. Colonoscopy is highly operator dependent, but systematic efforts to measure and improve quality are impacting performance. Colonoscopy holds a substantial advantage over other strategies for detection of serrated lesions, and a recent case-control study suggests that once-only colonoscopy or colonoscopy at 20-year intervals, by a high-level detector, could ensure lifetime protection from colorectal cancer for many patients.