Since health research has become increasingly acknowledged as an important tool for development, many approaches have been undertaken to understand national health research from a systems perspective. This paper reviews 28 case studies that describe or analyse health research systems in 26 low- and middle-income countries. These case studies were sponsored either by the Council on Health Research for Development or the South-East Asia Regional Office of the World Health Organization. In reviewing these case studies, we identify several common challenges facing national health research systems. These challenges include the lack of coordination in research activities; the inadequate participation of stakeholders in research, policy and implementation processes; the lack of demand for research and the low accessibility of research findings. These obstacles are compounded by some fundamental systems constraints, such as the lack of financial resources, human capacities, infrastructure and data. By identifying from these case studies the common challenges of health research systems as well as approaches to overcome these, this paper highlights the potential for case studies to inform policies and strategies for strengthening health research systems, and presents recommendations for future case studies to increase this potential.