The goal of comparative effectiveness research (CER) is to improve effectiveness, efficacy and efficiency in health care. While CER seems to present a major opportunity to introduce accountability into health care by identifying and promoting best practices in medicine, many issues surrounding CER remain poorly understood by clinicians and researchers, including what study designs are most appropriate for such research and what analytic tools are most helpful. The goal of this review is therefore to provide background and definitions of what constitutes CER and to discuss the various study designs and their strengths and weaknesses in achieving the stated goals of CER, while relating them to examples relevant to perioperative research. We provide a brief outline of the types of analytic methods particularly useful for CER and connect the reader to references for their practice. Finally, we assess the role of CER in perioperative research and provide some thoughts on future paths.