Colonoscopy with polypectomy has been established as the major prevention and detection strategy for colorectal cancer for over a decade. Over this period advances in colonoscopic imaging, polyp detection, prediction of histopathology and polypectomy techniques have all been seen; however, the true magnitude of the limitations of colonoscopy has only recently been widely recognized. The rate and location of missed or interval cancers after complete colonoscopy appears to be influenced by the operator-dependency of colonoscopy and failure of conventional practices to detect and treat adenomatous, and possibly more importantly, non-adenomatous colorectal cancer precursors. Consequently, studies that expand our understanding of these factors and advances that aim to improve colonoscopy, polypectomy, and cancer protection are of critical importance.