To provide decision makers with the best available evidence, the Agency for Healthcare Research and Quality established a network of Evidence-based Practice Centers across North America. The centers perform systematic reviews on important questions posed by partner organizations about clinical, organizational, and policy interventions in healthcare. The Agency works closely with partners and other decision maker s to help translate that evidence into practice or policy. In this paper, we review important lessons we have learned over the past 7 years about how to increase the efficiency and impact of systematic reviews. Lessons concern selecting the right topics and scope, working effectively with partners, and balancing consistency and flexibility in methods. We examine continuing evolutions of the program and the impact of planned work on comparative effectiveness performed as part of the Medicare Modernization Act of 2003.