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Through its impact on the adenoma-carcinoma sequence, colonoscopy has a central role in the detection and prevention of colorectal cancer (CRC). Observational data support a protective effect of colonoscopy and polypectomy on CRC incidence and mortality. However, recent studies suggest that the degree of CRC protection afforded by colonoscopy is dependent on the effectiveness of identification of prevalent cancers or their precursors, particularly in the proximal colon. Biologic variation in tumor genetics and growth likely contribute to diminished protection in the proximal colon. Operator variability is known to be a key factor predicting adenoma detection. Evidence supports the immediate adoption of specific quality improvement initiatives to reduce the failure rate of colonoscopy. Further interventions should target individual, organizational, and health system factors which influence physician behavior.