Comparative effectiveness research fundamentally reorients how clinical evidence is generated and used with the goal of providing actionable information to decision-makers. To achieve this, it is vital that decision-makers and the research enterprise are engaged from research inception, to evidence generation and translation. Practice-based research networks are affiliated clinicians in diverse communities with the goal of conducting research to improve care. Practice-based research networks have the potential to advance all phases of the comparative effectiveness research cycle. The aim of this paper is to explore current and potential roles of practice-based research networks in conducting comparative effectiveness research.