In 2005, the Agency for Healthcare Research and Quality established the Effective Health Care (EHC) Program. The EHC Program aims to provide understandable and actionable information for patients, clinicians, and policy makers. The Evidence-based Practice Centers are one of the cornerstones of the EHC Program. Three key elements guide the EHC Program and thus, the conduct of Comparative Effectiveness Reviews by the EPC Program. Comparative Effectiveness Reviews introduce several specific challenges in addition to the familiar issues raised in a systematic review or meta-analysis of a single intervention. The articles in this series together form the current Methods Guide for Comparative Effectiveness Reviews of the EHC Program.