Stroke is a tremendous burden to health worldwide both in the developed and developing world. Current levels of research funding do not adequately reflect this burden, particularly when expected increases in stroke rates are considered. Of course, an investment in stroke research is only justified if a return can be expected. The ultimate goal of stroke research is to reduce the burden of disease, and clinical trials are the clearest expression of the value of research because their results can directly impact health. In a review of stroke trials funded by the US National Institute of Neurological Disorders and Stroke, we found that the overall impact of the trials was dramatically positive and justified the entire research budget of the Institute. Nonetheless, there were obvious opportunities for improvement. Methods for selecting trials to fund could be improved and better aligned with disease burden and potential impact. Furthermore, clinical trial costs are increasing rapidly and reversing this trend must be a priority. More creative and systematic approaches to defining the research agenda and enhancing trial methods could substantially accelerate the rate of discovery and increase the impact of those discoveries on public health. To get there, we desperately need more research on research—meta-research—on topics not just relevant to stroke, but to the study of all disease.