Medical imaging is a prime example of an innovation that has brought important advances to medical care while triggering concerns about potential overuse and excessive costs. Many hopes are riding on comparative effectiveness research to help guide better decision making to improve quality and value. But the dynamic nature of medical imaging poses challenges for the traditional paradigms of evidentiary review and analysis at the heart of comparative effectiveness. This paper discusses these challenges and presents policy lessons for manufacturers, evidence reviewers, and decisionmakers, illustrated by an assessment of a prominent emerging imaging technique: computed tomography (CT) colonography.