Computed tomographic colonography, also called virtual colonoscopy, is an evolving technology under evaluation as a new method of screening for colorectal cancer. However, its performance as a test has varied widely across studies, and the reasons for these discrepancies are poorly defined. 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. Future investigations should demonstrate the influence of these potential factors on sensitivity of computed tomographic 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 computed tomographic colonography for colorectal cancer screening.