Research examining the process of deciding between treatment alternatives, the applicability of the existing literature to this process, and the way that this knowledge can be applied to inform clinical decisions is termed comparative effectiveness research (CER). Despite its emerging role in both clinical medicine and public policy, many neurosurgeons are unaware of the history of CER, the principles fundamental to its implementation, and the nature and extent to which it impacts patient care. We present a review of literature that provides a brief history of the evolution of CER, an overview of its scientific, financial, and public policy implications, and a discussion of its implementation and potential significance in modern clinical practice. We discuss how CER seeks to combine treatment efficacy data with quality of life, outcomes, and other forms of effectiveness data to guide selection of optimal patient management strategies. This research paradigm strengthens the final step in clinical research that should follow the traditional demonstration of efficacy and reemphasizes the potentially important role of observational and retrospective investigations in establishing effectiveness of efficacious procedures in actual application to individual patients. It is useful for neurosurgeons to understand the CER model, because it occupies an emerging role in both clinical medicine and public policy and presents a potentially useful model for informing medical decision-making in the type of real-world situations commonly encountered by clinical neurosurgeons.