Health system reforms across Africa, Asia and Latin America in recent decades demonstrate the value of health policy and systems research (HPSR) in moving towards the goals of universal health coverage in different circumstances and by various means. The role of evidence in policy making is widely accepted; less well understood is the influence of the concrete conditions under which HPSR is carried out within the national context and which often determine policy outcomes. We investigated the varied experiences of HPSR in Mexico, Cambodia and Ghana (each selected purposively as a strong example reflecting important lessons under varying conditions) to illustrate the ways in which HPSR is used to influence health policy. We reviewed the academic and grey literature and policy documents, constructed three country case studies, and interviewed two leading experts from each of Mexico and Cambodia and three from Ghana (using semi-structured interviews, anonymised to ensure objectivity). For the design of the study, design of the semi-structured questionnaire, and the analysis of results, we used a modified version of the context-based analytical framework developed by Dobrow et al., 2004.The results demonstrate that HPSR plays a varied but essential role in effective health policy making and that the use, implementation and outcomes of research and research-based evidence occurs inevitably within a national context that is characterised by political circumstances, the infrastructure and capacity for research, and the longer-term experience with HPSR processes. This analysis of national experiences demonstrates that embedding HPSR in the policy process is both possible and productive under varying economic and political circumstances. Supporting research structures with social development legislation, establishing relationships based on trust between researchers and policy makers, and building a strong domestic capacity for health systems research all demonstrate means by which the value of HPSR can be materialised in strengthening health systems.