Several studies have raised warnings about the limited effectiveness of colonoscopy for the prevention of colorectal cancer (CRC), especially of the proximal colon. Two major categories of factors might be responsible for the development of interval cancers, namely technical, endoscopist-dependent factors and biological characteristics of the cancer that lead to more rapid tumour progression. Recognition of endoscopist-dependent factors is critical, as these factors are probably amenable to correction through improved awareness and education of endoscopists, using quality metrics (such as adenoma detection rates and cecal intubation rates) for objective evaluation and feedback. In this article, the current literature regarding the incidence of, and potential explanations for, interval CRCs is outlined. Although there is probably an interaction between technical and biology-related factors--and an attempt to dissect the biology from the technology might be fraught with difficulties--a structured analysis of individual cases of interval cancer might help in the continuous monitoring of the quality of colonoscopy, and ultimately might reduce the number of interval CRCs.