Better estimates of changes in the level and structure of national, regional, and global expenditures on health research and development (R&D) are needed as an important source of information for advancing countries' health research policies. However, such estimates are difficult to compile and comparison between countries needs careful calibration. We outline the steps that need to be taken to make reliable estimates of trends in countries' expenditures on health R&D, describe that an ideal approach would involve the use of international sets of deflators and exchange rates that are specific to health R&D activities, and explain which methods should be used given the current absence of such health R&D-specific deflators and exchange rates. Finally, we describe what should be the way forward in improving our ability to make reliable estimates of trends in countries' health R&D expenditures.