Computed tomographic (CT) colonography has been advocated as an alternative colorectal screening method because studies in populations with a high prevalence of polyps have demonstrated that sensitivity for patients with large (> or =10 mm) polyps is generally high (approximately 90%). In three recent studies in low-prevalence populations, however, these values vary from 55% to 94%. Many questions have been raised as to the cause of this remarkable variability, which hampers the implementation of CT colonography in colorectal cancer screening and surveillance. We provide an overview of some potential causes and discuss the available, often indirect, evidence. In addition, several other obstacles that may influence implementation are discussed. Many differences between the study with high sensitivity (94%) and the two studies with low sensitivity (55% and 64%) exist: the primary method to review the data (two or three dimensional), bowel preparation (with or without oral contrast agents), study design (verification method and analysis of adenomas only), reader's experience, and scanning technique (single vs. multislice, thin vs. thick sections). Additional obstacles for implementation in prevention of colorectal cancer may be controversial results concerning patient acceptance, the large-scale use of ionizing radiation, difficulties in detecting flat adenomas, and extracolonic findings. Use of primary three-dimensional review methods, addition of oral contrast agents to bowel preparation, and endoscopic verification of false-positive results on CT colonography are speculated to have a positive influence on sensitivity. Future investigations should demonstrate the influence of these potential factors on sensitivity of CT colonography. Despite a growing body of evidence, it remains uncertain to what extent patient acceptance, radiation issues, flat lesions, and extracolonic findings will be a stumbling block to using CT colonography for colorectal cancer screening.