Health systems research is widely recognized as essential for strengthening health systems, getting costeffective treatments to those who need them, and achieving better health status around the world. However, there is significant ambiguity and confusion in this field’s characteristics, boundaries, definition and methods. Adding to this ambiguity are major conceptual barriers to the production, reproduction, translation and implementation of health systems research relating to both the complexity of health systems and research involving them. These include challenges with epistemology, applicability, diversity, comparativity and priority-setting. Three promising opportunities exist to mitigate these barriers and strengthen the important contributions of health systems research. First, health systems research can be supported as a field of scientific endeavour, with a shared language, rigorous interdisciplinary approaches, cross-jurisdictional learning and an international society. Second, national capacity for health systems research can be strengthened at the individual, organizational and system levels. Third, health systems research can be embedded as a core function of every health system. Addressing these conceptual barriers and supporting the field of health systems research promises to both strengthen health systems around the world and improve global health outcomes.