The increased demand for evidence-based health care practices calls for comparative effectiveness research (CER), namely the generation and synthesis of research evidence to compare the benefits and harms of alternative methods of care. A significant contribution of CER is the systematic identification and synthesis of available research studies on a specific topic. The purpose of this article is to provide an overview of methodological issues pertaining to systematic reviews and meta-analyses to be used by investigators with the purpose of conducting CER. A systematic review or meta-analysis is guided by a research protocol, which includes (a) the research question, (b) inclusion and exclusion criteria with respect to the target population and studies, © guidelines for obtaining relevant studies, (d) methods for data extraction and coding, (e) methods for data synthesis, and (f ) guidelines for reporting results and assessing for bias. This article presents an algorithm for generating evidence-based knowledge by systematically identifying, retrieving, and synthesizing large bodies of research studies. Recommendations for evaluating the strength of evidence, interpreting findings, and discussing clinical applicability are offered.