BackgroundWhile calls for promoting evidence-informed policymaking (EIP) have become stronger in recent years, there is a paucity of methods to prioritize issues for knowledge translation (KT) and EIP. As requested by WHO and as part of efforts to address this gap, we conducted a critical interpretive synthesis (CIS) to develop a conceptual framework that outlines the features of priority-setting processes and contextual factors influencing the prioritization of issues for KT efforts.MethodsWe systematically reviewed the literature and used an interpretive analytic approach—the CIS—to synthesize the results and develop the conceptual framework. We used a "compass" question to create a detailed search strategy and conducted electronic searches to identify papers based on their potential relevance to priority-setting for KT efforts and EIP.ResultsWe identified 161 eligible papers. Our findings on key features of the priority-setting process unpacked three 3 levels of constructs: ‘pathways’ for identifying and prioritizing policy issues for knowledge translation efforts; ‘phases’ within each pathway; and ‘steps’ for each phase. There are three main pathways: (1) explicit and systemic priority-setting processes involving policymakers and stakeholders to determine priority topics (collaborative); (2) a policymaker or stakeholder brings an issue forward or asks for evidence on a particular topic (demand-driven); and (3) a need or policy gap is identified by a knowledge translation platform (supply-driven). Within each pathway, four phases emerged: “Preparatory”, “prioritization”, “knowledge translation” and “scale-up and sustainability”. Across these phases, the following steps were identified: establishing a core team, defining a scope, confirming a timeline, sensitizing stakeholders, generating potential issues, gathering contextual information, setting guiding principles, selecting prioritization criteria, applying the method for prioritization, documenting and communicating priorities, validating and revising priorities, selecting venue for decision-making, implementing priorities, monitoring and evaluation, promoting institutionalization, and engaging in peer learning and exchange of experience. We identified engaging stakeholders and strengthening capacity as cross-cutting elements. Our findings on contextual factors unpacked four categories: (1) institutions; (2) ideas; (3) interests; and (4) external factors.ConclusionsThis CIS generated a multi-level conceptual framework for prioritizing issues for KT efforts and laid the foundation for a WHO tool that supports prioritization in practice. The study contributes meaningfully to both the literature and the operationalization of KT and EIP.