Comparative effectiveness research (CER) is increasingly popular, yet discussions of its conduct and consequences often overlook the extensive history of comparing different therapeutic options in patient-oriented research. In particular, research in the Department of Veterans Affairs (VA) has included a decades-long focus on generating information that can enhance medical decision making and improve health outcomes. Categories of such research include multisite randomized controlled trials (conducted by the Cooperative Studies Program) and observational studies involving either primary or secondary data collection. As representative examples from cardiology, a landmark VA clinical trial published in the 1970s evaluated the benefits of coronary artery bypass grafting surgery among patients with angina; a VA trial initiated in the 1990s, and identified formally as CER, demonstrated that percutaneous coronary intervention is not superior to optimal medical therapy; and a database investigation using information from the VA electronic medical record system in the 2000s found that use of proton pump inhibitor medication is associated with the attenuation of the benefits of clopidogrel among patients hospitalized for acute coronary syndrome. A review of these (and other) selected projects, based on their type of study design, serves to highlight the strengths, limitations, and potential of CER.