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There is good evidence that colorectal cancer (CRC) screening has been successful at reducing both CRC incidence and death. Colonoscopy, utilized as either a primary screening tool or a follow-up exam when other screening tests are positive, has significantly contributed to these encouraging trends. However, it is well recognized that colonoscopy is not perfectly sensitive for the detection of neoplasia and that CRC can be diagnosed within a short interval following a colonoscopy that did not detect one. The literature surrounding these cases has rapidly expanded over the last decade. Specifically, studies aimed at understanding the frequency of these events and the likely explanations for their occurrence have been performed. This review will highlight current knowledge around the epidemiology of interval post colonoscopy CRC (PCCRC). The common explanations for these cancers including missed lesions, new lesions, and incompletely resected lesions will be reviewed and their contribution to interval PCCRC estimated. Finally, the relationship of these putative explanations to potential opportunities to prevent interval PCCRC will be explored. Current approaches to prevention largely center on consistent adherence to quality colonoscopy standards. Future approaches include advances in technology to better visualize the colon and adequately resect detected neoplasia. Finally, improvement in training as well as development of a culture of continuous quality improvement will be essential to maximize the benefits of colonoscopy in daily clinical practice.